Biaryl substituted imidazole compounds useful as farnesyl-protein transferase inhibitors

ABSTRACT

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

RELATED APPLICATIONS

This application is a § 371 of PCT/US97/05383 filed Apr. 1, 1997. Thisapplication claims the benefit of U.S. provisional application No.60/014,592, filed Apr. 3, 1996, and U.S. provisional application No.60/022,582, filed Jul. 24, 1996.

BACKGROUND OF THE INVENTION

The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of asignalling pathway that links cell surface growth factor receptors tonuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a conformational change. The GTP-bound form of Raspropagates the growth stimulatory signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are found in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are defective in theirGTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochen. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also farnesylated. James, et al., havealso suggested that there are farnesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin four general classes (S. Graham, Expert Opinion Ther. Patents, (1995)5:1269-1285). The first are analogs of farnesyl diphosphate (FPP), whilea second class of inhibitors is related to the protein substrates (e.g.,Ras) for the enzyme. Bisubstrate inhibitors and inhibitors offarnesyl-protein transferase that are non-competitive with thesubstrates have also been described. The peptide derived inhibitors thathave been described are generally cysteine containing molecules that arerelated to the CAAX motif that is the signal for protein prenylation.(Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS,88:732-736 (1991)). Such inhibitors may inhibit protein prenylationwhile serving as alternate substrates for the farnesyl-proteintransferase enzyme, or may be purely competitive inhibitors (U.S. Pat.No. 5,141,851, University of Texas; N. E. Kohl et al., Science,260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). Ingeneral, deletion of the thiol from a CAAX derivative has been shown todramatically reduce the inhibitory potency of the compound. However, thethiol group potentially places limitations on the therapeuticapplication of FPTase inhibitors with respect to pharmacokinetics,pharmacodynamics and toxicity. Therefore, a functional replacement forthe thiol is desirable.

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 A1).

It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels (JPH7-112930).

It is, therefore, an object of this invention to develop low molecularweight compounds that will inhibit farnesyl-protein transferase andthus, the post-translational farnesylation of proteins. It is a furtherobject of this invention to develop chemotherapeutic compositionscontaining the compounds of this invention and methods for producing thecompounds of this invention.

SUMMARY OF THE INVENTION

The present invention comprises novel biaryl-containing compounds whichinhibit the farnesyl-protein transferase. Further contained in thisinvention are chemotherapeutic compositions containing these farnesyltransferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the formula A:##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the farnesylation of the oncogeneprotein Ras. In a first embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula A: ##STR2##wherein: R^(1a) and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, R¹¹ C(O)O--, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰--;

R², R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹¹ S(O)_(m) NR¹⁰ --,(R¹⁰)₂ NS(O)_(m) --, R¹³ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(6d) orR^(6e) is unsubstituted or substituted heterocycle, attachment of R²,R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ringis through a substitutable heterocycle ring carbon;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO, ##STR3## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, substituted heterocycleC₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ C(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is independently selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, halogen R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

R¹³ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, --CH₂ N(R¹⁰)₂, benzyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle;

X is a bond, --CH═CH--, O, --C(═O)--, --C(O)NR⁷ --, --NR⁷ C(O)--,--C(O)O--, --OC(O)--, --C(O)NR⁷ C(O)--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂-- or --S(═O)_(m) --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention is illustratedby the following formula: ##STR4## wherein: R^(1a) is independentlyselected from: hydrogen C₃ -C₁₀ cycloalkyl,

R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R², R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹¹ S(O)_(m) NR¹⁰ --,(R¹⁰)₂ NS(O)_(m) --, R¹³ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ C(O)--NR¹⁰ --;

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(6d) orR^(6e) is unsubstituted or substituted heterocycle, attachment of R²,R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ringis through a substitutable heterocycle ring carbon;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO, ##STR5## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is independently selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

R¹³ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, --CH₂ N(R¹⁰)₂, benzyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl orisoquinolinyl;

X is a bond, O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷ C(O)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

p is independently 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention areillustrated by the formula B: ##STR6## wherein: R^(1a) is independentlyselected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁-C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R² and R³ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹¹ S(O)_(m) NR¹⁰ --,(R¹⁰)₂ NS(O)_(m) --, R¹³ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R², R³, R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R², R³, R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring is through asubstitutable heterocycle ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

R¹³ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, --CH₂ N(R¹⁰)₂, benzyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, orS(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

Another preferred embodiment of the compounds of this invention areillustrated by the formula C: ##STR7## wherein: R^(1a) is independentlyselected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁-C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R² and R³ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹¹ S(O)_(m) NR¹⁰ --,(R¹⁰)₂ NS(O)_(m) --, R¹³ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R², R³, R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R², R³, R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring is through asubstitutable heterocycle ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

R¹³ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, --CH₂ N(R¹⁰)₂, benzyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR¹⁰C(O)--, --NR¹⁰ --or O; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula D: ##STR8##wherein: R^(1a) is independently selected from: hydrogen, C₃ -C₁₀cycloalkyl or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R³ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R², R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R², R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring is through asubstitutable heterocycle ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰), R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; or

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--;

n is 0 or 1; provided that n is not 0 if A¹ is a bond, O, --N(R¹⁰)--, orS(O)_(m) ;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In another more preferred embodiment of this invention, the inhibitorsof farnesyl-protein transferase are illustrated by the formula E:##STR9## wherein: R^(1a) is independently selected from: hydrogen, R¹⁰O--, --N(R¹⁰)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)--;

R² is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)₂, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ C(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstitstitued C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;

R³ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R², R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R², R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring is through asubstitutable heterocycle ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--;

n is 0 or 1;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula F: ##STR10##wherein: R^(1a) is independently selected from: hydrogen, C₃ -C₁₀cycloalkyl or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R³ is selected from H, halogen, CH₃ and CF₃ ;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R², R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R², R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring is through asubstitutable heterocycle ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula G: ##STR11##wherein: R^(1a) is independently selected from: hydrogen, R¹⁰ O--,--N(R¹⁰)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle or C₃ -C₁₀ cycloalkyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R³ is selected from H, halogen, CH₃ and CF₃ ;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R², R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R², R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring is through asubstitutable heterocycle ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

m is 0, 1 or 2; and

n is 0 or 1;

or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole

1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole

1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazol

1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazole

1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole

5-(4-Cyanophenyloxy)-1-(2'-methyl-4-biphenylmethyl)-imidazole

5-(4-Biphenyloxy)-1-(4-eyanobenzyl)-imidazole

5-(2'-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazole

5-(4-(3',5'-dichloro)biphenylmethyl)-1-(4-cyanobenzyl)imidazole

1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole

1-(4-Biphenylmethyl)-5-(1-(R,S)-hydroxy-1-(4-cyanophenyl)methylimidazole

1-(4-Biphenylmethyl)-5-(1-(R,S)-amino-1-(4-cyanophenyl) methylimidazole

1-(4-biphenylmethyl)-5-(1-(R,S)-methoxy-1-(4-cyanophenyl)-methylimidazole

1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(4-biphenyl)-methyl)imidazole

1-(4-Cyanobenzyl)-5-(1-oxo-1-(4-biphenyl)-methyl)imidazole

1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl)-imidazole

1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-biphenyl)methyl-imidazole

5-(2-[1,1'-Biphenyl]vinylene)-1-(4-cyanobenzyl)imidazole

1-(4-Biphenylmethyl)-5-(4-bromophenyloxy)-imidazole

1-(3'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(4'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(3'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole

1-(4'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole

1-(3'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'3'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'4'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(3'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) inidazole

1-(2'-Fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(4-(2'-Trifluoromethylphenyl)-2-Chlorophenylmethyl)-5-(4-cyanobenzyl)imidazole

1-{1-(4-(2'-trifluoromethylphenyl)phenyl)ethyl}-5-(4-cyanobenzyl)imidazole

1-(2'-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl) imidazole

1-(2'-N-t-Butoxycarbonylamino-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Acetylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole

1-(2'-Methylsulfonylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Ethylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole

1-(2'-Phenylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole

1-(2'-Glycinylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole

1-(2'-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl) imidazole

1-(2'-Methyl-4-biphenylmethyl)-4-chloro 5-(4-cyanobenzyl) imidazole

1-(3'-Chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole

1-(3'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyi)imidazole

1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole

1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(3'-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Chloro-4'-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Ethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-(2-Propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-(2-Methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(2'-Ethyl-4-biphenylmethyl)-5-(4-(1H-tetrazol-5-yl))benzyl)imidazole

1-[1-(4-Cyanobenzyl)imidazol-5-ylmethoxy]-4-(2'-methylphenyl)-2-(3-N-phthalimido-1-propyl)benzene

1-(3',5'-Ditrifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(3',5'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(3',5'-Dimethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole

1-(3-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

1-(4-Cyanobenzyl)-2-methyl-5-(2'-methylbiphenyl-4-yloxy)imidazole

5-(4-Cyanobenzyl)-1-(3-cyano-2'-trifluoromethylbiphenyl-4-ylmethyl)-imidazole

2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-cyanobenzyl)imidazole2-Amino-1-(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-Butylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole1-(3-Propylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole

1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazole1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazole

1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole

1-(4-Cyanobenzyl)-5-(4-biphenylmethyl)-2-methylimidazole

1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)]ethyl-2-methyl imidazole

1-(4-Cyanobenzyl-5-[1-(4-biphenyl)]vinylidene-2-methylimidazole and

1-(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylimidazole

or the pharmaceutically acceptable salts or optical isomers thereof.

Specific examples of the compounds of the invention are;

1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole ##STR12##1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole ##STR13##1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole ##STR14##1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl)imidazole##STR15## 5-(2'-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazole##STR16##1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl)-imidazole##STR17## 1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole##STR18## 1-(2',5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole##STR19##1-(3'-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole##STR20## or the pharmaceutically acceptable salts thereof.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. When any variable (e.g. aryl, heterocycle,R^(1a), R^(1b) etc.) occurs more than one time in any constituent, itsdefinition on each occurence is independent at every other occurence.Also, combinations of substituents/or variables are permissible only ifsuch combinations result in stable compounds.

As used herein, "alkyl" and the alkyl portion of aralkyl and similarterms, is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms; "alkoxy" represents an alkyl group of indicated number of carbonatoms attached through an oxygen bridge.

As used herein, "cycloalkyl" is intended to include non-aromatic cyclichydrocarbon groups having the specified number of carbon atoms. Examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number ofcarbon atoms and having one or several double bonds. Examples of alkenylgroups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,geranylgeranyl and the like.

"Alkynyl" groups include those groups having the specified number ofcarbon atoms and having one triple bonds. Examples of alkynyl groupsinclude acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.

"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl," and the aryl portion of aralkyl and aroyl, isintended to mean any stable monocyclic or bicyclic carbon ring of up to7 members in each ring, wherein at least one ring is aromatic. Examplesof such aryl elements include phenyl, naphthyl, tetrahydronaphthyl,indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. Examples ofsuch heterocyclic elements include, but are not limited to, azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, phthalimid-1-yl, pyridyl,pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl,thienofuryl, thienothienyl, and thienyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 members in each ring, wherein atleast one ring is aromatic and wherein from one to four carbon atoms arereplaced by heteroatoms selected from the group consisting of N, O, andS. Examples of such heterocyclic elements include, but are not limitedto, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, andthienyl.

As used herein in the definition of R⁷, the substituted C₁₋₈ alkyl,substituted C₃₋₆ cycloalkyl, substituted aroyl, substituted aryl,substituted heteroaroyl, substituted arylsulfonyl, substitutedheteroarylsulfonyl and substituted heterocycle include moietiescontaining from 1 to 3 substituents in addition to the point ofattachment to the rest of the compound.

As used herein, when no specific substituents are set forth, the terms"substituted aryl", "substituted heterocycle" and "substitutedcycloalkyl" are intended to include the cyclic group which issubstituted on a substitutable ring carbon atom with 1 or 2substitutents selected from the group which includes but is not limitedto F, Cl, Br, CF₃, NH₂, N(C₁ -C₆ alkyl)₂, NO₂, CN, (C₁ -C₆ alkyl)O--,--OH, (C₁ -C₆ alkyl)S(O)_(m) --, (C₁ -C₆ alkyl)C(O)NH--, H₂ N--C(NH)--,(C₁ -C₆ alkyl)C(O)--, (C₁ -C₆ alkyl)OC(O)--, N₃,(C₁ -C₆ alkyl)OC(O)NH--,phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl,furyl, isothiazolyl and C₁ -C₂₀ alkyl.

Lines drawn into the ring systems from substituents (such as from R²,R³, R⁴ etc.) indicate that the indicated bond may be attached to any ofthe substitutable ring carbon atoms.

The substituent illustrated by the structure ##STR21## is a simplifiedrepresentation of a phenyl ring having five (5) substituents (hydrogensand/or non-hydrogens) and may also be represented by the structure##STR22##

The moiety described as ##STR23## where any two of R^(6a), R^(6b),R^(6c), R^(6d) and R^(6e) on adjacent carbon atoms are combined to forma diradical selected from --CH═CH--CH═CH, --CH═CH--CH--, --(CH₂)₄ -- and--(CH₂)₄ -- includes the following structures: ##STR24## It isunderstood that such fused ring moieties may be further substituted bythe remaining R^(6a), R^(6b), R^(6c), R^(6d) and/or R^(6e) as definedhereinabove.

Preferably, R^(1a) and R^(1b) are independently selected from: hydrogen,R¹¹ C(O)O--, --N(R¹⁰)₂, R¹⁰ C(O)NR¹⁰ --, R¹⁰ O-- or unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted phenyl,--N(R¹⁰)₂, R¹⁰ O-- and R¹⁰ C(O)NR¹⁰ --.

Preferably, R² is selected from:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, CN, NO₂,R¹⁰ C(O)-- or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --.

Preferably, R³ is selected from: hydrogen, halogen, trifluoromethyl,trifluoromethoxy and C₁ -C₆ alkyl.

Preferably, R⁴ and R⁵ are hydrogen.

Preferably, R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independentlyselected from:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, CN, NO₂, R¹⁰ C(O)-- or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl, C₃ -C₁₀cycloalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)-- or --N(R¹⁰)₂ ; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --.

Preferably, R⁸ is independently selected from:

a) hydrogen, and

b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁ -C₆perfluoroalkyl or CN.

Preferably, R⁹ is hydrogen, halogen, CF₃ or methyl.

Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, A¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)-- and--N(R¹⁰)S(O)₂ --.

Preferably, V is selected from hydrogen, heterocycle and aryl. Morepreferably, V is phenyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl,pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W isselected from imidazolyl and pyridyl.

Preferably, X is a bond, --NR¹⁰ C(O)--, O or --C(═O)--. Most preferably,X is a bond.

Preferably, n and r are independently 0, 1, or 2.

Preferably s is 0.

Preferably t is 1.

Preferably, the moiety ##STR25## is selected from: ##STR26##

It is intended that the definition of any substituent or variable (e.g.,R^(1a), R⁹, n, etc.) at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. Thus,--N(R¹⁰)₂ represents --NHH, --NHCH₃, --NHC₂ H₅, etc. It is understoodthat substituents and substitution patterns on the compounds of theinstant invention can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be synthesizedby techniques known in the art, as well as those methods set forthbelow, from readily available starting materials.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared either by ion exchange chromatography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the Schemes 1-22, in addition toother standard manipulations such as ester hydrolysis, cleavage ofprotecting groups, etc., as may be known in the literature orexemplified in the experimental procedures. Substituents R², R⁶ and R⁸,as shown in the Schemes, represent the substituents R², R³, R⁴, R⁵,R^(6a), R^(6b), R^(6c), R^(6d) and R⁸ ; although only one such R², R⁶ orR⁸ is present in the intermediates and products of the schemes, it isunderstood that the reactions shown are also applicable when such arylor heteroaryl moieties contain multiple substituents.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. Aryl-aryl coupling is generally described in "ComprehensiveOrganic Functional Group Transformations," Katritsky et al. eds., pp472-473, Pergamon Press (1995).

Synopsis of Schemes 1-22:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 1-13 illustrate synthesis of the instant biaryl compound whichincorporate a preferred benzylimidazolyl sidechain. Thus, in Scheme 1,for example, a biaryl intermediate that is not commercially availablemay be synthesized by methods known in the art. Thus, a suitablysubstituted phenyl boronic acid I may be reacted under Suzuki couplingconditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substitutedhalogenated benzoic acid, such as 4-bromobenzoic acid, to provide thebiaryl carboxylic acid II. The acid may be reduced and the triflate ofthe intermediate alcohol III may be formed in situ and coupled to asuitably substituted benzylimidazolyl IV to provide, after deprotection,the instant compound V.

Schemes 2-5 illustrate other methods of synthesizing the key alcoholintermediates, which can then be processed as described in Scheme 1.Thus, Scheme 2 illustrates the analogous series of biaryl alcoholforming reactions starting with the halogenated biarylaldehyde.

Scheme 3 illustrates the reaction wherein the "terminal" phenyl moietyis employed in the Suzuki coupling as the halogenated reactant. Such acoupling reaction is also compatible when one of the reactantsincorporates a suitably protected hydroxyl functionality as illustratedin Scheme 4.

Negishi chemistry (i Org. Synth., 66:67 (1988)) may also be employed toform the biaryl component of the instant compounds, as shown in Scheme5. Thus, a suitably substituted zinc bromide adduct may be coupled to asuitably substituted aryl halide in the presence of nickel (II) toprovide the biheteroaryl VII. The aryl halide and the zinc bromideadduct may be selected based on the availability of the startingreagents.

Scheme 6 illustrates the preparation of a suitably substitutedbiphenylmethyl bromide which could also be utilized in the reaction withthe protected imidazole as described in Scheme 1.

Preparation of biaryl intermediates having a suitably substituted alkylmoiety on the carbon adjacent to the eventual point of attachment to therest of the instant compounds is illustrated in Scheme 6a. Thus asuitably substituted biaryl carboxylic acid is first converted to theamide and then the phenyl lithium is prepared and reacted in situ with asuitably substituted alkanal to provide the hydroxyalkane side-chain.The amide is then converted sequentially to the hydroxymethylbiaryl IIIaor bromomethylbiaryl intermediates which may then be utilized inreactions that have been previously described or will be describedbelow.

As illustrated in Scheme 7, the sequence of coupling reactions may bemodified such that the biphenyl bond is formed last. Thus, a suitablysubstituted imidazole may first be alkylated with a suitably substitutedbenzyl halide to provide intermediate VIII. Intermediate VIII can thenundergo Suzuki type coupling to a suitably substituted phenyl boronicacid.

Scheme 8 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole IX may be selectivelyiodinated to provide the 5-iodoimidazole X. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate XI. Intermediate XI can then undergo the alkylationreactions that were described hereinabove.

Scheme 9 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the biaryl via an alkyl amino,sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated biaryl moieties to provide the instant compoundsshown.

Compounds of the instant invention wherein the A¹ (CR^(1a) 2)_(n) A²(CR^(1a) 2)_(n) linker is oxygen may be synthesized by methods known inthe art, for example as shown in Scheme 10. The suitably substitutedphenol XIV may be reacted with methyl N-(cyano)methanimidate to providethe 4-phenoxyimidazole XV. After selective protection of one of theimidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Scheme 11 illustrates an analogous series of reactions wherein the(CR^(1b) 2)_(p) X(CR^(1b) 2)p linker of the instant compounds is oxygen.Thus, a suitably substituted haloaryl alcohol, such as, is reacted withmethyl N-(cyano)methanimidate to provide intermediate XVI. IntermediateXVI is then protected and, if desired to form a compound of a preferredembodiment, alkylated with a suitably protected benzyl. The intermediateXVII can then be coupled to a second aryl moiety by Suzuki chemistry toprovide the instant compound.

Compounds of the instant invention wherein the A¹ (CR^(1a) 2)_(n) A²(CR^(1a) 2)_(n) linker is a substituted methylene may be synthesized bythe methods shown in Scheme 12. Thus, the N-protected imidazolyl iodideXVIII is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol XIX. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 1) provides the instant compound XX. If other R¹ substituents aredesired, the acetyl moiety can be manipulated as illustrated in theScheme.

Grignard chemistry may also be employed to form a substituted alkyllinker between the biaryl and the preferred W (imidazolyl) as shown inScheme 13. Similar substituent manipulation as shown in Scheme 12 may beperformed on the fully functionalized compound which incorporates anR^(1b) hydroxyl moiety. ##STR27##

Schemes 16-20 illustrate reactions wherein the moiety ##STR28##incorporated in the compounds of the instant invention is represented byother than a substituted imidazole-containing group.

Thus, the intermediates whose synthesis are illustrated in Schemeshereinabove and other biheteroaryl intermediates obtained commerciallyor readily synthesized, can be coupled with a variety of aldehydes. Thealdehydes can be prepared by standard procedures, such as that describedby O. P. Goel, U. Krolls, M. Stier and S. Kesten in i Organic Syntheses,1988, 67, 69-75, from the appropriate amino acid (Scheme 14). Grignardchemistry may be utilized, as shown in Scheme 14, to incorporate thebiaryl moiety. Thus, a suitably substituted biaryl Grignard reagent isreacted with an aldehyde to provide the C-alkylated instant compoundXXI. Compound XXI can be deoxygenated by methods known in the art, suchas a catalytic hydrogention, then deprotected with trifluoroacetic acidin methylene chloride to give the final compound XXII. The final productXXII may be isolated in the salt form, for example, as atrifluoroacetate, hydrochloride or acetate salt, among others. Theproduct diamine XXII can further be selectively protected to obtainXXIII, which can subsequently be reductively alkylated with a secondaldehyde to obtain XXIV. Removal of the protecting group, and conversionto cyclized products such as the dihydroimidazole XXV can beaccomplished by literature procedures.

If the biaryl subunit reagent is reacted with an aldehyde which also hasa protected hydroxyl group, such as XXVI in Scheme 15, the protectinggroups can be subsequently removed to unmask the hydroxyl group (Schemes15, 16). The alcohol can be oxidized under standard conditions to e.g.an aldehyde, which can then be reacted with a variety of organometallicreagents such as Grignard reagents, to obtain secondary alcohols such asXXX. In addition, the fully deprotected amino alcohol XXXI can bereductively alkylated (under conditions described previously) with avariety of aldehydes to obtain secondary amines, such as XXXII (Scheme16), or tertiary amines.

The Boc protected amino alcohol XXVIII can also be utilized tosynthesize 2-aziridinylmethylbiaryl such as XXXIII (Scheme 17). TreatingXXVIII with, 1,1'-sulfonyldiimidazole and sodium hydride in a solventsuch as dimethylformamide led to the formation of aziridine XXXIII. Theaziridine is reacted with a nucleophile, such as a thiol, in thepresence of base to yield the ring-opened product XXXIV.

In addition, the biaryl subunit reagent can be reacted with aldehydesderived from amino acids such as O-alkylated tyrosines, according tostandard procedures, to obtain compounds such as XL, as shown in Scheme18. When R' is an aryl group, XL can first be hydrogenated to unmask thephenol, and the amine group deprotected with acid to produce XLI.Alternatively, the amine protecting group in XL can be removed, andO-alkylated phenolic amines such as XLII produced.

Schemes 19-22 illustrate syntheses of suitably substituted aldehydesuseful in the syntheses of the instant compounds wherein the variable Wis present as a pyridyl moiety. Similar synthetic strategies forpreparing alkanols that incorporate other heterocyclic moieties forvariable W are also well known in the art. ##STR29##

The instant compounds are useful as pharmaceutical agents for mammals,especially for humans. These compounds may be administered to patientsfor use in the treatment of cancer. Examples of the type of cancer whichmay be treated with the compounds of this invention include, but are notlimited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloidleukemias and neurological tumors. Such tumors may arise by mutations inthe ras genes themselves, mutations in the proteins that can regulateRas activity (i.e., neurofibromin (NF-1), neu, scI, abl, Ick, fyn) or byother mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of blindness related toretinal vascularization.

The compounds of this invention are also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, a component of NF-1is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certainviral infections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine,1:541-545(1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. i American Journalof Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEBJournal, 2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungalinfections.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the instant compounds may be useful in combination with knownanti-cancer and cytotoxic agents. Similarly, the instant compounds maybe useful in combination with agents that are effective in the treatmentand prevention of NF-1, restinosis, polycystic kidney disease,infections of hepatitis delta and related viruses and fungal infections.

If fomulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's blood-stream by local bolus injection.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known immunological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

Example 1 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloridesalt

Step A: 1-Trityl-4-(4-cyanobenzyl)-imidazole

To a suspension of activated zinc dust (3.57 g, 54.98 mmol) in THF (50mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reactionstirred under argon for 45 minutes, at 20° C. The suspension was cooledto 0° C. and a-bromo-p-tolunitrile (9.33 g, 47.6 mmol) in THF (100 mL)was added dropwise over a period of 10 minutes. The reaction was thenallowed to stir at 20° C. for 6 hours and bis(triphenylphosphine)NickelII chloride (2.40 g, 3.64 mmol) and 4-iodo-1-tritylimidazole (15.95 g,36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739 (1991)) were addedin one portion. The resulting mixture was stirred 16 hours at 20° C. andthen quenched by addition of saturated NH₄ Cl solution (100 mL) and themixture stirred for 2 hours. Saturated aq. NaHCO₃ solution was added togive a pH of 8 and the solution was extracted with EtOAc (2×250 mL),dried (MgSO₄) and the solvent evaporated in vacuo. The residue waschromatographed (Silica gel, 0-20% EtOAc in CH₂ Cl₂) to afford the titlecompound as a white solid.

¹ H NMR (CDCl₃, 400 Mz) δ (7.54 (2H, d, J=7.9 Hz), 7.38(1H, s),7.36-7.29 (11H, m), 7.15-7.09(6H, m), 6.58(1H, s) and 3.93(2H, s) ppm.

Step B: 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydochloridesalt

To 1-trityl-4-(4-Cyanobenzyl)-imidazole (608 mg, 1.43 mmol) inacetonitrile (2 mL) was added 4-chloromethylbiphenyl (290 mg, 1.43 mmol)and the mixture heated at 55° C. for 16 hours. The residue was dissolvedin methanol (30 ml) and heated at reflux for 20 minutes, cooled andevaporated to dryness. The residue was partitioned between sat. aq.NaHCO₃ solution and CH₂ C₁₂. The organic layer was dried, (MgSO₄) andthe solvent evaporated in vacuo. The residue was chromatographed (Silicagel, 5% MeOH in CH₂ Cl₂) to afford the imidazole which was converted tothe HCl salt by treatment with one equivalent of HCl in aqueousacetonitrile. Evaporation of solvent in vacuo afforded the titlecompound as a white powder.

Anal. Calcd for C₂₄ H₁₉ N₃ •1.00 HCl: C, 74.70; H, 5.22; N, 10.89.Found: C, 74.70; H, 5.31; N, 10.77. FAB MS 350 (MH⁺); ¹ H NMR CD₃ OD δ9.03(1H, s), 7.65-7.50(5H, m), 7.44(2H, t, J=7.5 Hz), 7.39(1H, s),7.35(1H, t, J=7.3 Hz), 7.26(2H, d, J=8.1 Hz), 7.20(2H, d, J=8.1 Hz),5.42(2H, s) and 4.17(2H, s) ppm.

Example 2 1-(2-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloridesalt

To 1-trityl-4-(4-cyanobenzyl)-imidazole (250 mg, 0.588 mmol) inacetonitrile (1 mL) was added 2(bromomethyl)biphenyl (0.108 mL, 0.591mmol) and the mixture heated at 55° C. for 16 hours. The solvent wasevaporated in vacuo. The residue was dissolved in methanol (10 mL) andheated at reflux for 30 minutes, cooled and the solvent evaporated invacuo. The residue was partitioned between sat. aq. NaHCO₃ solution andCH₂ Cl₂. The organic layer was dried, (NaSO₄) and the solvent evaporatedin vacuo. The residue was chromatographed (silica gel, 3% MeOH in CH₂Cl₂) to afford the imidazole, which was converted to the HCl salt bytreatment with one equivalent of HCl in aqueous acetonitrile.Evaporation of solvent in vacuo afforded the title compound as a whitesolid.

Anal. Calcd. for C₂₄ H₁₉ N₃ •1.00HCl: C, 74.70; H, 5.22; N, 10.89.Found: C, 74.60; H, 5.26; N, 10.97. FAB MS 350 (MH⁺); ¹ H NMR (CD₃ OD,400 MHz) δ 8.39(1H, s), 7.59(2H, d, J=8.4 Hz), 7.48(1H, t, J=6.5 Hz),7.46-7.36(3H, m), 7.30(1H, d, J=6.6 Hz), 7.28-7.18(3H, m), 7.13(2H, d,J=8.1 Hz), 5.31(2H, s) and 3.78(2H, s) ppm.

Example 3 1-(3-Biphenylmethyl)-5-(4-cyanobenzyl)imidazoletrifluoroacetate salt

Step A: 3-(Bromomethyl)biphenyl

To a solution of 3-phenyltoluene (1.80 mL, 10.9 mmol) in carbontetrachloride (50 mL) was added N-bromosuccinimide (2.124 g, 11.93 mmol)and the mixture heated to 70° C. AIBN (50 mg, 0.30 mmol) was added andthe mixture refluxed for 30 mins. Additional AIBN was added (50 mg, 0.30mmol) and the mixture refluxed for 16 hours. The reaction was cooled,filtered, and the solvent evaporated in vacuo. The residue waschromatographed (Silica gel, 5% EtOAc in hexanes) to afford the titlecompound as a white solid.

Step B: 1-(3-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole trifluoroacetatesalt

To 1-trityl-4-(4-cyanobenzyl)-imidazole (251 mg, 0.590 mmol) inacetonitrile (1 mL) was added 3-(bromomethyl)biphenyl (145 mg, 0.587mmol) and the mixture heated at 55° C. for 16 hours. The residue wasdissolved in methanol (10 mL) and heated at reflux for 30 minutes,cooled and evaporated to dryness. The residue was partitioned betweensat. aq. NaHCO₃ solution and CH₂ Cl₂. The organic layer was dried,(NaSO₄) and the solvent evaporated in vacuo. The residue waschromatographed (Silica gel, 2-5% MeOH in CH₂ Cl₂) and further purifiedby preparative HPLC, (gradient elution, 95:5 to 5:95% water:acetonitrilecontaining 0.1% trifluoroacetic acid) to afford the title compound.

Anal. Calcd. for C₂₄ H₁₉ N₃ •1.10 C₂ HO₂ F₃.0.65 H₂ O: C, 64.68; H,4.43; N, 8.64. Found: C, 64.68; H, 4.43; N, 8.50. FAB MS 350 (MH⁺); ¹ HNMR (CD₃ OD, 400 MHz) δ 9.05(1H, d, J=1.6 Hz), ), 7.58(1H, d, J=7.6 Hz),7.55-7.48(4H, m), 7.48-7.32(5H, m), 7.29(1H, s), 7.24(2H, d, 8.1 Hz),7.13(1H, dd, J=7.7 and 0.8 Hz), 5.46(2H, s) and 4.20(2H, s) ppm.

Example 4 1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole

Step A: 1-(4-Cyanobenzyl)-5-aminoethylimidazole

N^(G) -pivaloyloxymethyl-N^(a) -phthaloylhistamine¹ (4.55 g, 12.8 mmol)and a-bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved inacetonitrile (70 mL) and heated at 55° C. for 4 hours, cooled to roomtemperature, filtered and the imidazolium salt retained as a whitesolid. The filtrate was evaporated in vacuo to a volume of 30 mL andheated at 55° C. for 16 hours. The solution was cooled and the whitesolid collected by filtration. The solids were combined, and dissolvedin ethanol (50 mL). Hydrazine (0.287 mL, 9.06 mmol) was added and themixture heated at reflux for 16 hours. Dimethyl phthalate (2.22 mL,13.57 mmol) was added and reflux was continued for 6 hours. The reactionmixture was cooled to 0° C., the solid was removed by filtration,concentrated to dryness, and the residue chromatographed (Silica gel, 3%CH₂ Cl₂ then 8% NH₄ OH in CH₃ OH) to afford the title compound.

¹ H NMR (CD₃ OD, 400 MHz) δ 7.76 (1H, s), 7.74 (2H, d, J=8 Hz, ), 7.27(2H, d, J=8 Hz), 6.88 (1H, s), 5.35 (2H, s), 2.76 (2H, t, J=6 Hz) and2.60(2H, t, J=6 Hz) ppm. 1. C. Emmett, F. H. Holloway, and J. L. Turner,J. Chem. Soc., Perkin Trans. 1, 1341, (1979))

Step B: 1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole

To a solution of 1-(4-cyanobenzyl)-5-aminoethylimidazole (107 mg, 0.358mmol), 4-phenylbenzoic acid (70.9 mg, 0.358 mmol),3-hydroxy-1,2,3-benzotriazin-4(3H)-one, (72.6 mg, 0.445 mmol) andtriethylamine (0.215 mL, 1.54 mmol) in DMF (4.0 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDC, (83.3mg, 0.435 mmol) and the mixture stirred for 16 hours at ambienttemperature. The reaction was partitioned between sat. aq. NaHCO₃solution and EtOAc. The organic layer was dried, (Na₂ SO₄) and thesolvent evaporated in vacuo. The residue was chromatographed (Silicagel, 5% MeOH in CH₂ Cl₂) to afford the imidazole which was converted tothe HCl salt by treatment with one equivalent of HCl in aqueousacetonitrile. Evaporation of the solvent in vacuo afforded the titlecompound as a white solid.

Anal. Calcd. for C₂₆ H₂₂ N₄ O.1.00 HCl.0.95 H₂ O: C, 67.88; H, 5.46; N,12.18. Found: C, 67.83; H, 5.47; N, 11.97. FAB MS 407 (MH⁺); ¹ H NMR(CD₃ OD, 400 MHz) δ 9.00(1H, s),), 8.67(1H, m), 7.90-7.60(8H,m),7.58-7.30(6H, m), 5.65(2H, s), 3.65(2H, t, J=5.4 Hz) and 2.95(2H, t,J=6.4 Hz) ppm.

Example 51-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Step A: 4-(2-trifluoromethylphenyl)benzoic acid

To a solution of 4-carboxybenzeneboronic acid (1.218 g, 7.340 mmol) andNa₂ CO₃ (2.40 g, 22.6 mmol) in water (75 mL) was added p-dioxane (75mL). This mixture was treated sequentially with 2-iodobenzotrifluoride(1.05 mL, 7.48 mmol) and palladium (II) acetate (151 mg, 0.673 mmol) andallowed to stir at ambient temperature for 16 hours. The solvent wasevaporated in vacuo. To the residue was added EtOAc (400 mL) and water(300 mL). The aqueous layer was acidified to pH 1 with 1.0 N aq. HCl andthe layers separated. The aqueous layer was extracted with EtOAc (2×200mL). The organic extracts were combined, washed with brine (200 mL), 5%aq. Na₂ S₂ O₃ (200 mL), saturated NaCl (200 mL), dried (Na₂ SO₄), andthe solvent evaporated in vacuo to afford the title compound as a yellowsolid. ¹ H NMR (CDCl₃, 400 MHz) d 8.14(2H, d, J=8.1 Hz), ), 7.77(1H, d,J=7.9 Hz), 7.60(1H, t, J=7.5 Hz), 7.52(1H, t, J=7.3 Hz), 7.44(2H, d,J=8.1 Hz) and 7.33(1H, d, J=7.5 Hz) ppm.

Step B: 4-(2'-trifluoromethylphenyl)benzylalcohol

To a solution of 4-(2'-trifluoromethylphenyl)benzoic acid (1.525 g,5.728 mmol) in THF (25 mL) at 0° C. was added 1.0 M lithium aluminumhydride in tetrahydrofuran (12.0 mL, 12.0 mmol) over 10 minutes. Thereaction was allowed to stir at ambient temperature for 3 hours, cooledto 0° C., and quenched by dropwise addition of water (0.5 mL), 4 N aq.NaOH (0.5 mL), and water (1.5 mL). The reaction was filtered through apad of Celite and the filtrate evaporated in vacuo. The residue waschromatographed (Silica gel, 20% EtOAc in hexanes) to afford the titlecompound.

¹ H NMR (CDCl₃, 400 MHz) δ 7.74(1H, d, J=7.7 Hz), ), 7.55(1H, d, J=7.4Hz), 7.47(1H, t, J=7.4 Hz), 7.41(2H, d, J=7.9 Hz), 7.36-7.30(3H, m) and4.78(2H, s) ppm.

Step C:1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

To a solution of 4-(2'-trifluoromethylphenyl) benzylalcohol (362 mg,1.44 mmol) and diisopropylethylamine (0.260 mL, 1.49 mmol) indichloromethane (6.0 mL) at -78° C. was added trifluoromethanesulfonicanhydride (0.250 mL, 1.49 mmol) and the mixture stirred at -78° C. for 1hour. To this mixture was added a solution of1-trityl-4-(4-cyanobenzyl)-imidazole (613 mg, 1.44 mmol) indichloromethane (6.0 mL). The mixture was allowed to warm to ambienttemperature and stirred for 2 hours. The solvent was evaporated invacuo. The residue was dissolved in methanol (15 mL), heated at refluxfor 1 hour, and the solvent evaporated in vacuo. The residue waspartitioned between CH₂ Cl₂ and sat. aq. NaHCO₃ solution. The organiclayer was dried, (Na₂ SO₄) and the solvent evaporated in vacuo. Theresidue was chromatographed (Silica gel, 0-2% MeOH in CH₂ Cl₂) andfurther purified by preparative HPLC, (gradient elution, 95:5 to 5:95%water:acetonitrile containing 0.1% trifluoroacetic acid) to afford thetrifluoroacetic acid salt. The salt was partitioned between EtOAc andsat. aq. NaHCO₃ solution, the organic layer dried, (Na₂ SO₄) and thesolvent evaporated in vacuo to afford the imidazole. The amine wasconverted to the HCl salt by treatment with 1.0 equivalent of HCl inaqueous acetonitrile. Evaporation of the solvent in vacuo afforded thetitle compound as a white solid.

Anal. Calcd. for C₂₅ H₁₈ N₃ F₃.1.00 HCl.0.85 H₂ O: C, 64.00; H, 4.45; N,8.96. Found: C, 64.05; H, 4.24; N, 8.80. FAB MS 418 (MH⁺); ¹ H NMR (CD₃OD, 400 MHz) δ 9.10(1H, s), ), 7.78(1H, d, J=7.1 Hz), 7.70-7.62(3H, m),7.56(1H, t, J=7.5 Hz), 7.43(1H, s), 7.38-7.24(5H, m), 7.19(2H, d, 8.1Hz)), 5.48(2H, s) and 4.18(2H, s) ppm.

Example 6 1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole hydrochloridesalt

Step A: 4-Biphenylethanol

The 4-biphenylethanol was prepared using the protocol described inexample 5, step B and 4-biphenylacetic acid.

¹ H NMR (CDCl₃, 400 MHz) δ 0.60-7.55(4H, m), 7.43(2H, t, J=7.8 Hz),7.37-7.28(3H, m), 3.91(2H, q, J=6.4 Hz), 2.92(2H, t, J=6.6 Hz), 1.40(1H,t, J=5.8 Hz) ppm.

Step B: 1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole hydrochloridesalt

The title compound was prepared using the protocol described in example5, step C and 4-biphenylethanol

Anal. Calcd. for C₂₅ H₂₁ N₃.1.00 HCl.0.30 H₂ O: C, 74.08; H, 5.62; N,10.37. Found: C, 74.40; H, 5.52; N, 9.98. FAB MS 364 (MH⁺); ¹ H NMR(CDCl₃, 400 MHz) δ 8.78(1H, d, J=1.6 Hz), 7.70(2H, d, J=8.2 Hz),7.62-7.54(4H, m), 7.48-7.30(5H, m), 7.20-7.12(3H, m), 4.43(2H, t, J=6.9Hz), 4.04(2H, s), and 3.10(2H, t, J=6.8 Hz) ppm.

Example 7 1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Step A: 4-(2'-Bromophenyl)benzaldehyde

To a solution of 4-formylbenzeneboronic acid (1.19 g, 7.96 mmol) and Na₂CO₃ (1.68 g, 15.8 mmol) in water (60 mL) was added p-dioxane (60 mL).This mixture was treated sequentially with 2-bromo iodobenzene (2.25 g,7.95 mmol) and palladium (II) acetate (159 mg, 0.708 mmol) and allowedto stir at ambient temperature for 16 hours. The solvent was evaporatedin vacuo. To the residue was added EtOAc (400 mL) and water (300 mL).The aqueous layer was extracted with EtOAc (2×200 mL). The organicextracts were combined, washed with brine (200 mL), 5% aq. Na₂ S₂ O₃(200 mL), brinel (200 mL), dried, (Na₂ SO₄) and the solvent evaporatedin vacuo to afford the title compound which was used in the next stepwithout further purification.

Step B: 4-(2'-Bromophenyl)benzyl alcohol

To a solution of 4-(2'-bromophenyl)benzaldehyde 1.55 g, 7.95 mmol) inethanol (15 mL) at 0° C. was added sodium borohydride (2.22 g, 58.7mmol) and the reation stirred for 1 hour. The reaction was quenched withsaturated aq. NH₄ Cl and extracted into diethyl ether. The organicextracts were washed with brine, dried, (Na₂ SO₄) and evaporated invacuo. The residue was purified by chromatography (Silica gel, 25% EtOAcin hexanes) to afford the title compound as a colourless oil.

¹ H NMR (CDCl₃, 400 MHz) δ 7.66(1H, dd, J=8.1 and 1.1 Hz), 7.45-7.30(6H,m), 7.23(1H, m) and 4.66(2H, s) ppm.

Step C: 1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazolehydrochloride salt

The title compound was prepared using the protocol described in example5, step C and 4-(2'-bromophenyl) benzyl alcohol.

Anal. Calcd. for C₂₄ H₁₈ N₃ Br.100 HCl.1.46H₂ O: C, 58.70; H, 4.50; N,8.56. Found: C, 58.66; H, 4.10; N, 8.27. FAB MS 430(MH⁺); ¹ H NMR (CD₃OD 400 MHz) δ 9.11(1H, s), 7.68(1H, d, J=8.1 Hz), 7.62(2H, d, J=8.3 Hz),7.50-7.16(10H, m), 5.48(2H, s) and 4.20(2H, s) ppm.

Example 8 1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in example5, steps A-C using 2-iodotoluene.

Anal. Calcd. for C₂₅ H₂₁ N₃.1.00 HCl.0.65 H₂ O: C, 73.13; H, 5.47; N,10.23. Found: C, 73.16; H, 5.70; N, 10.20. ¹ H NMR (CD₃ OD 400 MHz) δ9.06(1H, d, J=1.6 Hz), 7.62(2H, d, J=8.4 Hz), 7.42(1H, s),7.35-7.10(10H, m), 5.44(2H, s), 4.21(2H, s) and 2.20(3H, s) ppm.

Example 9 1-(2'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt

The title compound was prepared using the protocol described in example5, steps A≧C using 2-trifluoromethoxyiodobenzene.

¹ H NMR (CD₃ OD 400 MHz) δ 9.08(1H, d, J=1.6 Hz), 7.61(2H, d, J=8.4 Hz),7.52-7.38(7H, m), 7.29(2H, d, J=8.1 Hz), 7.23(2H, d, J=8.1 Hz), 5.47(2H,s) and 4.17(2H, s) ppm.

Example 101-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in example5, steps A-C using 3,5-dichloroiodobenzene.

Anal. Calcd. for C₂₄ H₁₇ N₃ Cl₂.1.00 HCl.0.35 H₂ O: C, 62.52; H, 4.09;N, 9.11. Found: C, 62.57; H, 3.88; N, 9.04. FAB MS 418(MH⁺); ¹ H NMR(CD₃ OD 400 MHz) δ 9.08(1H, s), 7.57(6H, m), 7.44(2H, d, J=4.2 Hz),7.32-7.20(4H, m), 5.46(2H, s) and 4.17(2H, s) ppm.

Example 11 1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in example5, steps A-C using 2-methoxyiodobenzene.

Anal. Calcd. for C₂₅ H₂₁ N₃ O.100 HCl: C, 72.19H, 5.33; N, 9.79. Found:C, 72.12; H, 5.31; N, 10.10. ¹ H NMR (CD₃ OD, 400 MHz) δ 9.05(1H, d,J=1.3 Hz), 7.60(2H, d, J=7.2 Hz), 7.44(2H, d, J=8.2 Hz), 7.41 (1H, s),7.38-7.20(4H, m), 7.16(2H, d, J=8.1 Hz), 7.07(1H, d, J=8.0 Hz), 7.01(1H,t, J=7.5 Hz), 5.42(2H, s), 4.19(2H, s) and 3.80(3H, s) ppm.

Example 12 1-(2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in example5, steps A-C using 2-chloro iodobenzene.

Anal. Calcd. for C₂₄ H₁₈ N₃.1.00 HCl.0.20H₂ O: C, 68.05 H, 4.61; N,9.91. Found: C, 68.00; H, 4.77; N, 9.56. ¹ H NMR (CD₃ OD, 400 MHz) δ9.09(1H, d, J=1.3 Hz), 7.61(2H, d, J=7.2 Hz), 7.55-7.25(9H, m), 7.20(2H,d, J=8.1 Hz), 5.47(2H, s) and 4.21(2H, s) ppm.

Example 13 1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrobromide salt

Step A: 2-Chloro-4-phenyl toluene

A mixture of 2-chloro-4-iodotoluene(2.94 g, 11.63 mmol), phenyl boronicacid (1.56 g, 12.79 mmol), barium hydroxide (5.50 g, 17.44 mmol), DME (3mL) and water (15 mL) was purged with dry argon.Tetrakis(triphenyl-phosphine)palladium(O) (672 mg, 0.58 mmol) was added,and the resultant solution was stirred at 80° C. for 4 hours. Thesolvents were evaporated in vacuo, and the residue partitioned betweenEtOAc and water and acidified with 1M aq. HCl. The aqueous extract wasseparated, and extracted with EtOAc. The organic extracts were combined,washed with NaHCO₃ and 5% aq. Na₂ S₂ O₃, dried, (Na₂ SO₄) filtered andthe solvent evaporated in vacuo. The residue was purified bychromatography (Silica gel, 10% EtOAc in hexanes) to afford the titlecompound. ¹ H NMR (CDCl₃ 400 MHz) δ 7.62-7.54 (3H, m), 7.48-7.25(5H, m)and 2.43(3H, s) ppm.

Step B: 1-(Bromomethyl)-2-chloro-4-biphenyl

To a solution of 2-chloro-4-phenyl toluene (911 mg, 4.50 mmol) in carbontetrachloride (18 mL) was added N-bromosuccinimide (800 mg, 4.50 mmol)and the mixture heated to 70° C. AIBN (16.4 mg, 0.10 mmol) was added andthe mixture refluxed for 2 hours. The reaction was cooled, filtered, andthe solvent evaporated in vacuo. The residue was chromatographed (Silicagel, 15% CH₂ Cl₂ in hexanes) to afford the title compound as a whitesolid.

¹ H NMR (CDCl₃, 400 MHz) δ 7.62(1H, d, J=1.7 Hz), 7.60-7.34(7H, m) and4.65(2H, s) ppm.

Step C: 1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazolehydrobromide salt.

A suspension of 1-(bromomethyl)-2-chloro-4-biphenyl (500 mg, 1.78 mmol),1-trityl-4-(4-cyanobenzyl)-imidazole (756 mg, 1.78 mmol) in acetonitrile(5 mL) was stirred at 55° C. for 16 hours. The solvent was evaporated invacuo and the residue dissolved in methanol and stirred at reflux for 1hour. The solvent was evaporated in vacuo. The residue suspended inEtOAc (10 mL) and the product isolated as a white solid by filtration.The solids were washed with EtOAc (5 mL) and diethylether (10 mL) anddried in vacuo.

Anal. Calcd. for C₂₄ H₁₈ N₃ Cl.1.00 HBr.0.30H₂ O C, 61.31 H, 4.20 N,8.94. Found: C, 61.61; H, 4.23; N, 8.55. ¹ H NMR (CD₃ OD, 400 MHz) δ8.99(1H, d, J=1.4 Hz), 7.65(1H, d, J=2.3 Hz), 7.62-7.54(4H, m),7.54-7.43(4H, m), 7.40(1H, m), 7.29(2H, d, J=8.4 Hz), 7.11(1H, d, J=7.8Hz), 5.52(2H, s) and 4.24(2H, s) ppm.

Example 14 1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in example13, steps A-C using 3-chloro-4-iodotoluene. The imidazole was isolatedby chromatography (Silica gel, 2-3% MeOH in CH₂ Cl₂), and converted tothe HCl salt by treatment with HCl gas in EtOAc and evaporation of thesolvent in vacuo.

Anal. Calcd. for C₂₄ H₁₈ ClN₃.1.00 HCl.0.30H₂ O: C, 67.71H, 4.64; N,9.87. Found: C, 67.75; H, 4.69; N, 9.73. ¹ H NMR (CD₃ OD, 400 MHz) δ9.19(1H, s), 7.58(2H, d, J=8.0 Hz), 7.55-7.30(6H, m), 7.30-7.00(5H, m),5.45(2H, s) and 4.23(2H, s) ppm.

Example 151-(4-(3',5'-Bis-tifluoromethyl)-biphenymethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt

Step A: Methyl 4-(3',5'-Bis-trifluoromethylphenyl)benzoate

To a solution of 3',5'-Bis-trifluoromethylbenzeneboronic acid (0.430 g,1.57 mmol) and barium hydroxide octahydrate (0.675 g, 2.14 mmol) inwater (1.5 mL) was added DME (5 mL). This mixture was treatedsequentially with methyl-4-iodobenzoate (0.375 g, 1.43 mmol) andtetrakis triphenylphosphine palladium (0) (83 mg, 0.07 mmol) and heatedat 80° C. for 5 hours. The reaction cooled, acidified to pH 1 with aq.HCl and extracted with EtOAc (2×50 mL) The combined organic extractswere washed with sat. aq. NaHCO₃, brine, dried, (Na₂ SO₄) and thesolvent evaporated in vacuo. The residue was dissolved in methanol (50mL), saturated with gasseous HCl and stirred for 16 hours at ambienttemperature. The solvent was evaporated in vacuo to afford the titlecompound as a solid. ¹ H NMR (CDCl₃, 400 MHz) δ 8.17(2H, d, J=8.4 Hz),8.04(2H, s), 7.91(1H, s), 7.68(2H, d, J=8.4 Hz) and 3.97(3H, s) ppm.

Step B:1-(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in example5, steps B-C using methyl-{4-(3',5'-bistrifluoromethylphenyl)benzoate.

Anal. Calcd. for C₂₆ H₁₇ N₃ F₆.1.80 HCl C, 60.69; H, 3.49; N, 8.17.Found: C, 60.69; H, 3.35; N, 7.92. FAB MS 486(MH⁺); ¹ H NMR (CD₃ OD,400MHz) δ 9.70(1H, d, J=1.4 Hz),8.16(2H, s), 7.98(1H, s), 7.68(2H, d, J=8.4Hz), 7.57(2H, d, J=8.4 Hz), 7.43(1H, s), 7.27(4H, m), 5.47(2H, s) and4.17(2H, s) ppm.

Example 161-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazolehydrochloride salt

Step A: 4-Iodo-5-methylimidazole

To a solution of 4-methyl imidazole(8.20 g, 100 mmol) and sodiumcarbonate (21.2 g, 200 mmol) in water (650 mL) was added a solution ofsodium iodide (26.5 g, 180 mmol) and iodine (25.4 g, 100 mmol) in water(350 mL) over 90 minutes at room temperature. The reaction was stirred afurther 30 minutes and filtered. The resulting white solid was washedwith water and dried in vacuo at 50° C.

¹ H NMR (CD₃ OD 400 MHz) d 7.57 (1H, s) 4.86(1H, brs) and 2.20(3H,s)ppm.

Step B: 1-Trityl-4-iodo-5-methylimidazole

To a cold (0° C.) solution of 4-iodo-5-methylimidazole (5.0 g, 24.0mmol) and triethylamine (5.0 mL, 36.0 mmol) in CH₂ Cl₂ (100 mL) and1,4-dioxane (50 mL) was added trityl chloride (8.0 g, 29.0 mmol). Theresultant mixture was stirred for 2 hours and quenched with ice andextracted with diethyl ether. The organic extracts were washed with sat.aq. NaHCO₃, dried (K₂ CO₃) and the solvent evaporated in vacuo. Theproduct mixture was concentrated onto silica gel and chromatographed(Silica gel, 30-50% EtOAc in hexanes) to afford the title compound as apale yellow powder.

¹ H NMR (CDCl₃, 400 MHz) δ 7.43(1H, s), 7.35-7.30 (9H, m), 7.25-7.10(6H, m) and 2.27(3H, s) ppm.

Step C: 1-Trityl-4-(4-cyanobenzyl)5-methylimidazole

To a suspension of activated zinc dust (0.262 g, 3.99 mmol) in THF (1mL) was added dibromoethane (0.035 mL, 0.039 mmol) and the reactionstirred under argon at 20° C. for 45 minutes. The suspension was cooledto 0° C. and a-bromo-p-tolunitrile (0.51 g, 2.60 mmol) in THF (3 mL) wasadded dropwise over a period of 10 minutes. The reaction was thenallowed to stir at 20° C. for 45 minutes andbis(triphenylphosphine)Nickel II chloride (0.130 g, 0.399 mmol) and5-iodo-1-trityl imidazole (15.95 g, 36.6 mmol) were added in one portionThe resulting mixture was stirred 3 hours at 20° C. and then quenched byaddition of saturated NH₃ solution (2 mL) and the mixture stirred for 3hours, extracted with EtOAc (2×25 mL), dried (MgSO₄) and the solventevaporated in vacuo. The residue was chromatographed (Silica gel, 20%EtOAc in CH₂ Cl₂ to afford the title compound as a white solid.

¹ H NMR (CD₃ OD, 400 MHz) δ 7.62 (2H, d, J=8.3 Hz), 7.40-7.34(9H, m),7.31(2H, d, J=8.3 Hz), 7.26(1H, s), 7.18-7.10(6H, m), 3.93(2H, s), and1.41(3H, s) ppm.

Step D:1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazolehydrochloride salt

The title compound was prepared using the protocol described in example5, step C using 1-trityl-4-(4-cyanobenzyl)-5-methylimidazole.

Anal. Calcd. for C₂₆ H₂₀ N₃ F₃.1.00 HCl C, 66.74 H, 4.52; N, 8.98.Found: C, 66.42; H, 4.42; N, 8.86. ¹ H NMR (CD₃ OD 400 MHz) δ 8.98(1H,s), 7.77(1H, d, J=7.8 Hz), 7.66(1H, t, J=7.5 Hz), 7.62-7.50(3H, m),7.35-7.00(7H, m), 5.37(2H, 4.20(2H, s) and 2.34(3H, s) ppm.

Example 17 1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole

Step A: 5-(4-Cyanophenyloxy)imidazole

Sodium metal (1.10 g, 47.8 mmol) was dissolved in anhydrous methanol and4-cyanophenol (5.70 g, 47.8 mmol) was added. The resultant solution wasconcentrated and dried under vacuum overnight. A mixture of this sodiumsalt and 4-cyanophenol (25 g, mp 110-113° C.) was heated to 125-130° C.and neat methyl N-(cyanomethyl)methanimidate (5.0 g, 51 mmol; Hosmane,R. S. et al, J. Org. Chem., 1212, 1984) was added dropwise over a periodof 10 minutes under a slow stream of dry argon. The resultant mixturewas stirred at 120° C. for 2 hours, cooled, and the reaction productpartitioned between methylene chloride (500 mL) and aqueous sodiumhydroxide (1 M, 500 mL). The aqueous layer was separated and extractedwith methylene chloride (3×100 mL). The organic extracts were combined,washed with brine (100 mL), dried (K₂ CO₃), and the solvent evaporatedin vacuo. The residue was purified by chromatography (Silica gel, 3:7acetone in CHCl₃) to afford the title compound as a white powder.

¹ H NMR (DMSO-d₆ 400 MHz) δ 7.79 (2H, d, J=9.0 Hz), 7.54 (1H, s), 7.11(2H, d, J=9.0 Hz) and 6.96 (1H, s) ppm.

Step B: 4-(4-Cyanophenyloxy)-1-trityl-imidazole

To a cold (0° C.) solution of 4-(4-cyanophenyloxy)-imidazole (155 mg,0.84 mmol) and triethylanine (0.129 mL, 0.92 mmol) in DMF (1 mL) wasadded trityl chloride (245 mg, 0.88 mmol). The resultant mixture wasstirred at ambient temperature for 5 days. The product mixture wasconcentrated onto silica gel, chromatographed (Silica gel, 1:9 acetonein CHCl₃) to afford the title compound as a white powder.

¹ H NMR (CDCl₃ 400 MHz) δ 7.57 (2H, d, J=9.0 Hz), 7.38 (1H, s),7.35-7.09 (16H, m), 7.08 (2H, d, J=9.0 Hz) and 6.54(1H, s) ppm.

Step C: 1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole

The title compound was prepared u:sing the protocol described in example5, step C using 4-biphenyl methanol and substituting4-(4-cyanobenzyl)-1-trityl-imidazole with4-(4-cyanophenyloxy)-1-trityl-imidazole. The title compound was purifiedby chromatography (Silica gel 3:7 acetone in CHCl₃) and obtained as awhite solid.

Anal. Calcd for C₂₃ H₁₇ N₃ O•0.35 H₂ O: C, 77.23; H, 4.99; N, 11.75.Found: C, 77.30; H, 4.95; N, 11.58. ¹ H NMR (CDCl₃, 400 MHz) δ 7.80-7.35(10 H, m), 7.16 (2H, d, J=8.1 Hz), 7.01(2H, d, J=8.8 Hz), 6.74 (1H, s)and 4.98 (2H, s) ppm.

Using the same procedure but substituting4-(2-trifluoromethylphenyl)-benzylalcohol for biphenylmethanol in Step Cthe following compound was prepared:

1-(4-(2-trifluoromethylphenyl)phenylmethyl)-5-(4-cyanophenyloxy)-imidazole

Anal. Calcd for C₂₄ H₁₆ N₃ OF₃ •0.3 H₂ O: C, 67.86; H, 3.94; N, 9.89.Found: C, 67.85; H, 3.84; N, 9.73.

Using the same procedure but substituting 4-bromophenol for4-cyanophenol in Step A the following compound was prepared:

1-(4-Biphenylmethyl)-5-(4-bromophenyloxy)-imidazole

Anal. Calcd for C₂₂ H₁₇ BrN₂ O: C, 65.20; H, 4.23; N, 6.91. Found: C,65.26; H, 4.33; N, 6.80.

Example 185-(4-Cyanophenyloxy)-1-(2'-methyl-4-biphenylniethyl)-imidazolehydrochloride salt

The title compound was prepared using the protocol described in example17, step C, substituting 4-biphenylmethanol with2'-methyl-4-biphenylmethanol. The hydrochloride salt was obtained bytreatment of a solution of the imidazole in acetonitrile with aq. HCland evaporation of the solvents in vacuo.

Anal. Calcd for C₂₃ H₁₇ N₃ O•0.58 H₂ O•1.45 HCl: C, 67.23; H, 5.08; N,9.80. Found: C, 67.30; H, 5.08; N, 9.74. ¹ H NMR CDCl₃ δ 7.56 (2H, d,J=6.9 Hz), 7.46 (1H, s), 7.26-7.10 (8H, m), 7.02 (2H, d, J=8.8 Hz), 6.75(1H, s), 4.99 (2H, s) and 2.19 (3H, s) ppm.

Example 19 5-(4-Biphenyloxy)-1-(4-cyanobenzyl)-imidazoletrifluoroacetate salt

Step A: 4-(4-Bromophenyloxy)imidazole

The title compound was prepared as white solid using the protocoldescribed in example 17--step A, substituting 4-cyanophenol with4-bromophenol, and performing the reaction at 100-110° C.

¹ H NMR (DMSO-d₆ 400 MHz) δ 7.49(1H, s), 7.48(2H, d, J=9.0 Hz), 6.93(2H,d, J=9.0 Hz) and 6.85(1H, s) ppm.

Step B: 4-(4-Bromophenyloxy)-1-trityl-imidazole

The title compound was prepared as white solid using the protocoldescribed in example 17--step B, using 4-(4-bromophenyloxy) imidazole.

Step C: 5-(4-Bromophenyloxy)-1-(4-cyanobenzyl)-imidazole

The title compound was prepared as a white solid using the protocoldescribed in example 5, step C using, 4-cyanobenzyl alcohol and4-(4-bromophenyloxy)-1-trityl-imidazole. The title compound was purifiedby chromatography (Silica gel 3:7 acetone in CHCl₃).

¹ H NMR (CDCl₃ 400 MHz) δ 7.61(2H, d, J=8.1 Hz), 7.38(2H, d, J=9.0 Hz),7.37(1H, s), 7.21(2H, d, J=9.0 Hz), 6.63(1H, s) and 5.03(2H, s) ppm.

Step D: 5-(4-Biphenyloxy)-1-(4-cyanobenzyl)-imidazole trifluoroacetatesalt

A mixture of 5-(4-bromophenyloxy)-1-(4-cyanobenzyl)-imidazole (100 mg,0.28 mmol), phenyl boronic acid (69 mg, 0.56 mmol), K₃ PO₄ (240 mg, 1.13mmol), and DMF (5 mL) was purged with dry argon for a period of 15minutes. Tetrakis(triphenylphosphine)palladium(0) (33 mg, 0.028 mmol)was added, and the resultant solution was stirred at 80° C. for 18hours. The solvents were evaporated in vacuo, and the residuepartitioned between CH₂ Cl₂ and water. The aqueous extract wasseparated, and extracted with CH₂ Cl₂. The organic extracts werecombined, dried (Na₂ SO₄, filtered and evaporated in vacuo. The residuewas purified by chromatography (Silica gel, eluting with 3:7 acetone inCHCl₃, and the trifluoroacate salt obtained by treatment of a solutionof the imidazole in acetonitrile with aqueous TFA and evaporation of thesolvents in vacuo.

Anal. Calcd for C₂₃ H₁₇ N₃ O•1.25 TFA: C, 62.01; H, 3.72; N, 8.51.Found: C, 61.99; H, 3.69; N, 8.13. ¹ H NMR (CDCl₃, 400 MHz) δ 7.60(2H,d, J=8.3 Hz), 7.54-7.32(8H, m), 7.23(2H, d, J=8.5 Hz), 7.00(2H, d, J=8.8Hz), 6.72(1H, s) and 5.06 (2H, s) ppm.

Example 20 5-(2'-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazoletrifluoroacetate salt

The title compound was prepared as a white solid using the protocoldescribed in example 19--step D, substituting phenyl boronic acid witho-tolylboronic acid, and stirring the reaction mixture at 100° C. for 24hours.

Anal. Calcd for C₂₄ H₁₉ N₃ O•1.30 TFA•0.75 H₂ O: C, 60.72; H, 3.98; N,7.99. Found: C, 60.77; H, 4.00; N, 7.76. ¹ H NMR (CDCl₃ 400 MHz) δ7.61(2H, d, J=8.5 Hz), 7.41(1H, s), 7.27-7.18(8H, m), 6.98(2H, d, J=8.8Hz),6.70 (1H, s), 5.08(2H, s) and 2.25(3H, s) ppm.

Example 215-(4-(3',5'-dichloro)biphenylmethyl)-1-(4-cyanobenzyl)imidazolehydrochloride salt

Step A: 4-(3',5'-Dichlorophenyl) benzyl alcohol

The title compound was prepared using the protocol described in example5, steps A-B using 3,5-dichloroiodobenzene.

¹ H NMR (CDCl₃, 400 MHz) δ 7.54(2H, dt, J=8.20 and 2.0 Hz),7.48-7.43(4H, m), 7.33(1H, t, J=2.0 Hz), 4.76(2H, d, J=5.9 Hz) and1.68(1H, t, J=5.9 Hz) ppm.

Step B: 4-(3',5'-Dichlorophenyl) benzyl bromide

To a solution of triphenylphospine (636 mg, 2.42 mmol) and carbontetrabromide (830 mg, 2.50 mmol) in diethyl ether (5 mL) was added asolution of 4-(3',5'-bis-chlorophenyl) benzyl alcohol (50 mg, 1.98 mmol)in CH₂ Cl₂ (12 mL). The reaction was stirred at ambient temperature for16 hours, silica gel was than added and the solvent evaporated in vacuo.The product was isolated by chromatography (Silica gel, 10-30% EtOAc inhexanes) and obtained as a white solid.

¹ H NMR (CDCl₃, 400 MHz) δ 7.54-7.46(4H, m), 7.46-7.43(2H, m), 7.35(1H,m) and 4.54(2H, s) ppm.

Step C: 1-Trityl-4-(4-(3',5'-dichloro)-biphenylmethyl-imidazole

To a suspension of activated zinc dust (0.080 g, 1.22 mmol) in THF (0.25mL) was added dibromoethane (0.011 mL, 0.122 mmol) and the reactionstirred under argon at 20° C. for 45 minutes. 4-(3',5'-Dichlorophenyl)benzyl bromide (0.250 g, 0.791 mmol) in THF (1 mL) was added dropwiseover a period of 10 minutes. The reaction was then allowed to stir at20° C. for 45 minutes and bis(triphenylphosphine) Nickel II chloride(0.04 g, 0.031 mmol) and 4-iodo-1-trityl-imidazole (15.95 g, 36.6 mmol)were added in one portion. The resulting mixture was stirred 16 hours at20° C. and then quenched by addition of sat. aq. NH₄ Cl solution (2 mL)and the mixture stirred for 3 hours, extracted with EtOAc (2×25 mL),dried (MgSO₄) and the solvent evaporated in vacuo. The residue waschromatographed (Silica gel, 30-50% EtOAc in CH₂ Cl₂) to afford thetitle compound as a white solid.

¹ H NMR (CDCl₃, 400 MHz) δ 7.50-7.28 (15H, m), 7.18-7.10(6H, m),6.59(1H, s) and 3.93(2H, s) ppm.

Step D: 5-(4-(3',5'-Dichloro)-biphenylmethyl)-1-(4-cyanobenzyl)imidazole hydrochloride salt

A suspension of 4-cyanobenzyl bromide (19.1 mg, 0.097 mmol) and thetrityl derivative from step C (52.5 mg, 0.096 mmol) in acetonitrile (0.4mL) was stirred at 55° C. for 16 hours. The solvent was evaporated invacuo and the residue dissolved in methanol (4 mL) and stirred at refluxfor 1 hour. The solvent was evaporated in vacuo and partitioned betweenEtOAc and sat. aq. NaHCO₃ the organic layer was dried, (Na₂ SO₄) andevaporated in vacuo. The residue was chromatograped (Silica gel, 2% MeOHin CH₂ Cl₂), to afford the imidazole, which was dissolved inacetonitrile and converted to the HCl salt by addition of 1 equivalentof 1 M HCl. Evaporation of the solvent in vacuo afforded the titlecompound as a white solid.

¹ H NMR (CD₃ OD 400 MHz) δ 8.97(1H, s), 7.63(2H, d, J=8.2 Hz), 7.53(2H,s), 7.48(2H, d, J=8.2 Hz), 7.42(2H, s), 7.21(2H, d, J=8.0 Hz), 7.18(2H,d, J=8.2 Hz), 5.49(2H, s) and 4.07(2H, s) ppm.

Example 221-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazolehydrochloride salt

Step A: 1-Trityl-4-(1-(R,S)-hydroxy-1-(4-cyanophenyl) methylimidazole

To a solution of 1-trityl-4-iodoimidazole¹ (10 g, 23 mmol) in CH₂ Cl₂(93 mL) at room temperature was added ethyl magnesium bromide (8.4 mL ofa 3M solution in diethyl ether) and the reaction stirred for 2 hours.4-Cyanobenzaldehyde (3.36g, 25.21 mmol) was added and the reactionstirred a further 16 hours. The reaction was quenched with sat. aq. NH₄Cl and stirred until homogeneous. The pH was adjusted to 8.5 with sat.aq. NaHCO₃ and extracted with CH₂ Cl₂. The combined organic extractswere washed with brine, dried (MgSO₄) and the solvent evaporated invacuo. The resulting white solid was suspended in EtOAc (200 mL) andcollected by filtration.

¹ H NMR (CDCl₃, 400 MHz) δ 7.60(2H, d, J=8.2 Hz), 7.52(2H, d, J=8.2 Hz),7.41(1H, d, J=1.4 Hz), 7.38-7.20(9H, m), 7.15-7.02(6H, m), 6.62(1H, s),5.79(1H, d, J=4.6 Hz), and 3.11(1H, d, J=4.6 Hz) ppm. 1Journal ofOrganic Chemistry 56, 5739, 1991.

Step B: 1-Trityl-4-(1-(R,S)-acetoxy-1-(4-cyanophenyl) methylimidazole

A solution of1-trityl-4-(1-(R,S)-hydroxy-1-(4-cyanophenyl)methylimidazole (2.00 g,4.53 mmol), pyridine (1.10 mL) and acetic anhydride (0.641 mL) in DMF(20 mL) at room temperature was stirred for 16 hours. The reaction wasquenched with sat. aq. NaHCO₃ (50 mL) and water (50 ml), extracted withethyl acetate dried, (MgSO₄) and the solvent evaporated in vacuo. Theresulting solids were washed with diethylether to provide the titlecompound as an off white solid.

¹ H NMR (CDCl₃, 400 MHz) δ 7.62(2H, d, J=8.4 Hz), 7.53(2H, d, J=8.2 Hz),7.39(1H, d, J=1.3 Hz), 7.38-7.28(9H, m), 7.15-7.02(6H, m), 6.78(2H, s)and 2.12(3H, s) ppm.

Step C:1-(4-Biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazolehydrochloride salt

The title compound was prepared using the protocol described in example5, step C using1-trityl-4-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole and4-biphenylmethanol.

Anal. Calcd. for C₂₆ H₂₁ N₃ O₂.1.00 HCl.0.55H₂ O C, 68.81H, 5.13 N,9.26. Found: C, 68.98; H, 5.22; N, 8.87. FAB MS 408(MH⁺); ¹ H NMR (CD₃OD 400 MHz) δ 9.09(1H, s), 7.70(2H, d, J=8.4 Hz), 7.61(4H, t, J=8.2 Hz),7.45(1H, s), 7.45(4H, t, J=8.2 Hz), 7.36(1H, t, J=7.3 Hz), 7.23(2H, d,J=8.3 Hz), 7.05(1H, s), 5.54(2H, d, J=2.2 Hz) and 1.96(3H, s) ppm.

Example 23 1-(4-Biphenylmethyl)-5-(1-(R,S)-hydroxy-1-(4-cyanophenyl)methylimidazole hydrochloride salt

To a solution of1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole,from example 22, (389 mg 0.955 mmol) in THF (5 mL) at 0° C. was addedlithium hydroxide (0.192 mL), 0.192 mmol)and the reaction stirred atroom temperature for 3 hours. EtOAc (75 mL) and water (25 mL) were addedand the organic layer separated, dried (MgSO₄) and the solventevaporated in vacuo. The residue was purified by chromatography (Silicagel, 5% MeOH in CH₂ Cl₂) and converted to the HCl salt by treatment withHCl in EtOAc and evaporation of the solvent in vacuo.

Anal. Calcd. for C₂₄ H₁₉ N₃ O.0.70 HCl C, 73.73H, 5.08 N, 10.75. Found:C, 73.76; H, 5.17; N, 10.58. ¹ H NMR (CD₃ OD, 400 MHz) δ 8.57(1H, s),7.67(2H, d, J=8.4 Hz), 7.63-7.56(4H, m), 7.51(2H, d, J=8.0 Hz), 7.44(2H,t, J=7.4 Hz), 7.35(1H, t, J=7.5 Hz), 7.23(2H, d, J=8.2 Hz), 7.05(1H, s),5.94(1H, s), 5.50(1H, d, J=15.4 Hz) and 5.45(1H, d, J=15.4 Hz) ppm.

Example 24 1-(4-Biphenylmethyl)-5-(1-(R,S)-amino-1-(4-cyanophenyl)methylimidazole hydrochloride salt

A solution of1-(4-biphenylmethyl)-5-(1-(R,S)-hydroxy-1-(4-cyanophenyl)methylimidazole(49.0 mg, 0.122 mmol) in thionyl chloride (5 mL) at room temperature wasstirred for 45 minutes. The solvent was evaporated in vacuo and theresidue was treated with 4M NH₃ in MeOH and the solution stirred for 1hour and the solvents evaporated in vacuo. The residue was purified bychromatography (Silica gel, 2-5% NH₄ OH in acetonitrile) and convertedto the HCl salt by treatment with HCl in acetonitrile and evaporation ofthe solvent in vacuo.

Anal. Calcd. for C₂₄ H₂₀ N₄ 2.35HCl C, 64.04H, 5.00 N, 12.45. Found: C,64.13; H, 4.98; N, 12.43. ¹ H NMR (CD₃ OD 400 MHz) δ 9.20(1H, s),7.93(1H, s), 7.64(2H, d, J=8.4 Hz), 7.54(2H, d, J=7.3 Hz), 7.48-7.40(4H,m), 7.36(3H, m), 7.09(2H, d, J=8.2 Hz), 5.98(1H, s), 5.54(1H, d, J==14.9Hz) and 5.45(1H, d, J=14.9 Hz) ppm.

Example 251-(4-biphenylmethyl)-5-(1-(R,S)-methoxy-1-(4-cyanophenyl)-methylimidazole

The title compound was obtained as a minor component by the protocoldescribed in example 24.

¹ H NMR (CD₃ OD 400 MHz) δ 7.76(2H, d, J=8.2 Hz), 7.75(1H, s), 7.64(2H,d, J=7.6 Hz), 7.58(2H, d, J=8.2 Hz), 7.50-7.40(4H, m), 7.36(1H, t, J=7.5Hz), 7.13(2H, d, J=7.9 Hz), 6.56(1H, s), 5.47(1H, s), 5.25(1H, d, J=15.4Hz), 5.20(1H, d, J=15.4 Hz) and 3.17(3H, s) ppm.

Example 26 1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(4-biphenyl)-methylimidazole

Step A: 1-Triphenylmethyl-4-(hydroxymethyl)imidazole

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260mmol) in 250 mL of dry DMF at room temperature was added triethylamine(90.6 mL, 650 mmol), a white solid precipitated from the solution.Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL ) was addeddropwise. The reaction mixture was stirred for 20 hours, poured overice, filtered, and washed with ice water. The resulting product wasslurried with cold dioxane, filtered, and dried in vacuo to provide thetitled product as a white solid which was sufficiently pure for use inthe next step.

Step B: 1-Triphenylmethyl-4-(acetoxymethyl)imidazole

Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mLof pyridine. Acetic anhydride (74 mL, 780 mmol) was added dropwise, andthe reaction was stirred for 48 hours during which it becamehomogeneous. The solution was poured into 2 L of EtOAc, washed withwater (3×1 L), 5% aq. HCl (2×1 L), sat. aq. NaHCO₃, and brine, and thendried, (Na₂ SO₄) and concentrated in vacuo to provide the crude product.The acetate was isolated as a white powder which was sufficiently purefor use in the next reaction.

Step C: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide

A solution of the product from Step B (85.8 g, 225 mmol) anda-bromo-p-tolunitrile (50.1 g, 232 mmol) in EtOAc (500 mL ) was stirredat 60° C. for 20 hours, during which a pale yellow precipitate formed.The reaction was cooled to room temperature and filtered to provide thesolid imidazolium bromide salt. The filtrate was concentrated in vacuoto a volume 200 mL, heated at 60° C. for two hours, cooled to roomtemperature, and filtered. The filtrate was concentrated in vacuo to avolume 100 mL, then heated at 60° C. for two hours, cooled to roomtemperature, and concentrated in vacuo to provide a pale yellow solid.All of the solid material was combined, dissolved in methanol (500 mL),and warmed to 60° C. After two hours, the solution was concentrated invacuo to provide a white solid which was triturated with hexane toremove soluble materials. Evaporation of residual solvent in vacuoprovided the titled product hydrobromide as a white solid which was usedin the next step without further purification.

Step D: 1-(4-Cyanobenzyl)-5-(hydroxymethyl)imidazole

To a solution of the acetate from Step C (50.4 g, 150 mmol) in 1.5 L of3:1 THF/water at 0° C. was added lithium hydroxide monohydrate (18.9 g,450 mmol). After one hour, the reaction was concentrated in vacuo,diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO₃ andbrine. The solution was then dried, (Na₂ SO₄) filtered, and concentratedin vacuo to provide the crude product as a pale yellow fluffy solidwhich was sufficiently pure for use in the next step without furtherpurification.

Step E: 1-(4-Cyanobenzyl)-5-imidazole carboxaldehyde

To a solution of the alcohol from Step D (21.5 g, 101 mmol) in DMSO (500mL) at room temperature was added triethylamine (56 mL, 402 mmol), thenSO₃ -pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reactionwas poured into 2.5 L of EtOAc, washed with water (4×1 L) and brine,dried, (Na₂ SO₄), and concentrated in vacuo to provide the aldehyde as awhite powder which was sufficiently pure for use in the next stepwithout further purificaton.

Step F: 1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(4-biphenyl)-methyl imidazole

A Grignard reagent, freshly prepared from 4-bromobiphenyl (116 mg, 0.500mmol) and magnesium turnings (11 mg, 0.73 mmol) in dry THF (0.50 mL) wasadded to a dry Argon-purged 3 mL flask containing the1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (105 mg, 0.50 mmol) in dryTHF (0.2 mL) with vigorous stirring at room temperature. After 1 hourthe reaction was quenched with sat. aq. NH₄ Cl (5 mL) and distributedbetween EtOAc (50 mL) and H₂ O (50 mL). The organic phase was evaporatedin vacuo and the residue chromatographed (Silica gel, 5% MeOH in CHCl₃)to afford the title compound.

Anal. Calcd for C₂₄ H₁₉ N₃ O•0.10 CHCl₃ •0.10 CH₃ OH: C, 76.37H, 5.16;N, 11.04. Found: C, 76.13; H, 5.10; N, 10.76. FAB MS 366 (MH⁺).

Example 27 1-(4-Cyanobenzyl)-5-(1-oxo-1-(4-biphenyl)-methyl imidazole

The alcohol from example 26 (105 mg, 0.228 mmol) in dioxane (3 mL) andactivated manganese dioxide (300 mg) and the mixture was stirred atreflux for 2 hours. The mixture was filtered and the clear filtrate wasevaporated and the residue chromatographed (Silica gel, 3% MeOH inCHCl₃) to afford the title compound.

Anal. Calcd for C₂₄ H₁₇ N₃ O•0.35 CHCl₃ : C, 72.17; H, 4.32; N, 10.37.Found: C, 71.87; H, 4.45; N, 10.29.

Example 28 1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methylimidazole

A Grignard reagent, freshly prepared from 4-bromo-2-fluorobiphenyl] (251mg, 1 mmol) and magnesium turnings (36 mg, 1.45 mmol) in dry THF (1 mL)was added to a dry argon-purged 5 mL flask containing1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (212 mg, 1 mmol) in dry THF(0.40 mL) with vigorous stirring at room temperature. After 1 hour thereaction was quenched with sat. aq. NH₄ Cl (10 mL) and distributedbetween EtOAc (100 mL) and H₂ O (50 mL). The organic phase wasevaporated and the residue was chromatographed (Silica gel, 5% MeOH inCHCl₃) to afford the title compound.

Anal. Calcd for C₂₄ H₁₈ N₃ OF•0.05 CHCl₃ : C, 74.18; H, 4.67; N, 10.79.Found: C, 74.13; H, 4.97; N, 10.48. FAB MS 384(MH⁺); ¹ H NMR (CDCl₃, 400MHz) δ 5.25(2H, d, J=3.6 Hz), 5.78 (1H, s), 6.84 (1H, s), 7.04-7.13 (4H,m), 7.30-7.39(2H, m) and 7.45-7.55 (7H, m) ppm.

Example 29 1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-biphenyl)methyl-imidazole

A Grignard reagent, freshly prepared from 3-biphenylbromide (116 mg,0.50 mmol) and magnesium turnings (18 mg, 0.73 mmol) in dry THF (0.5 mL)was added to a dry Argon-purged 3 mL flask containing1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (105 mg, 0.50 mmol) in dryTHF (0.20 mL) with vigorous stirring at room temperature. After 1 hourthe reaction was quenched with sat. NH₄ Cl (5 mL) and distributedbetween EtOAc (50 mL) and H₂ O (50 mL). The organic phase was evaporatedand the residue chromatographed (Silica gel, 5% MeOH in CHCl₃) to affordthe title compound.

Anal. Calcd for C₂₄ H₁₉ N₃ O•0.10 CHCl₃ :•0.15CH₃ OH: C, 75.34 H, 5.10;N, 10.87. Found: C, 75.25 H, 5.13; N, 10.48. FAB MS 366 (MH⁺); ¹ H NMR(CDCl₃, 400 MHz) δ 5.23 (2H, d,J=3.6 Hz), 5.78 (1H, s), 6.81(1H, s),7.02(2H, d, J=3.6 Hz), 7.26 (2H, d, J=3.6 Hz) 7.32-7.37(3H, m) and7.39-7.52 (7H, m) ppm.

Example 30 5-(2-[1,1'-Biphenyl]vinylene)-1-(4-cyanobenzyl)imidazoletrifluoroacetic acid salt

A mixture of 4-biphenyl bromide (260 mg, 1.1 mmol),5-vinyl-1-(4-cyanobenzyl)imidiazole (248 mg, 1 mmol), palladium (II)acetate (10 mg), tri-o-tolylphosphine (30 mg), methylamine (500 mL) inDMF (1 mL) was heated at 95° C. for 20 hours. The dark solution wascooled and chromatographed (Silica gel, 1% MeOH in CHCl₃) to yield crudeproduct which was further purified by preparative HPLC, (gradientelution, 95:5 to 5:95% water:acetonilrile containing 0.1%trifluoroacetic acid) to afford the title compound as a white solid.

Anal. Calcd. for C₂₄ H₁₉ N₃.1.40 C₂ HO₂ F₃ : C, 64.07; H, 3.95; N, 8.06.Found: C, 64.05; H, 3.99; N, 7.68. FAB MS 362 (MH⁺).

Example 311-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4-phenylbenzene

Step 1: Preparation of 1-triphenylmethyl-4-(hydroxymethyl)-imidazole

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35 g) in 250mL of dry DMF at room temperature was added triethylamine (90.6 mL). Awhite solid precipitated from the solution. Chlorotriphenylmethane (76.1g) in 500 mL of DMF was added dropwise. The reaction mixture was stirredfor 20 hours, poured over ice, filtered, and washed with ice water. Theresulting product was slurried with cold dioxane, filtered, and dried invacuo to provide the titled product as a white solid which wassufficiently pure for use in the next step.

Step 2: Preparation of 1-triphenylmethyl-4-(acetoxymethyl)-imidazole

The product from Step 1 was suspended in 500 mL of pyridine. Aceticanhydride (74 mL) was added dropwise, and the reaction was stirred for48 hours during which it became homogeneous. The solution was pouredinto 2 L of EtOAc, washed with water (3×1 L), 5% aq. HCl soln. (2×1 L),sat. aq. NaHCO₃, and brine, then dried (Na₂ SO₄), filtered, andconcentrated in vacuo to provide the crude product. The titled acetateproduct was isolated as a white powder (85.8 g) which was sufficientlypure for use in the next step.

Step 3: Preparation of 1-(4-cyanobenzyl)-5-(acetoxymethyl)imidazolehydrobromide

A solution of the product from Step 2 (85.8 g) and α-bromo-p-tolunitrile(50.1 g) in 500 mL of EtO Ac was stirred at 60° C. for 20 hours, duringwhich a pale yellow precipitate formed. The reaction was cooled to roomtemperature and filtered to provide the solid imidazolium bromide salt.The filtrate was concentrated in vacuo to a volume 200 mL, reheated at60° C. for two hours, cooled to room temperature, and filtered again.The filtrate was concentrated in vacuo to a volume 100 mL, reheated at60° C. for another two hours, cooled to room temperature, andconcentrated in vacuo to provide a pale yellow solid. All of the solidmaterial was combined, dissolved in 500 mL of methanol, and warmed to60° C. After two hours, the solution was reconcentrated in vacuo toprovide a white solid which was triturated with hexane to remove solublematerials. Removal of residual solvents in vacuo provided the titledproduct hydrobromide as a white solid (50.4 g, 89% purity by HPLC) whichwas used in the next step without further purification.

Step 4: Preparation of 1-(4-cyanobenzyl)-5-(hydroxymethyl)-imidazole

To a solution of the acetate from Step 3 (50.4 g) in 1.5 L of 3:1THF/water at 0° C. was added lithium hydroxide monohydrate (18.9 g).After one hour, the reaction was concentrated in vacuo, diluted withEtOAc (3 L), and washed with water, sat. aq. NaHCO₃ and brine. Thesolution was then dried (Na₂ SO₄), filtered, and concentrated in vacuoto provide the crude product (26.2 g) as a pale yellow fluffy solidwhich was sufficiently pure for use in the next step without furtherpurification.

Step 5: Preparation of 1-(4-cyanobenzyl)-5-imidazole-carboxaldehyde

To a solution of the alcohol from Step 4 (21.5 g) in 500 mL of DMSO atroom temperature was added triethylamine (56 mL), then SO₃ -pyridinecomplex (40.5 g). After 45 minutes, the reaction was poured into 2.5 Lof EtOAc, washed with water (4×1 L) and brine, dried (Na₂ SO₄),filtered, and concentrated in vacuo to provide the titled aldehyde (18.7g) as a white powder which was sufficiently pure for use in the nextstep without further purification.

Step 6: Preparation of1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4-phenylbenzene

To a solution of 1-amino-3-methoxy-4-phenylbenzene in 1,2-dichloroethaneat 0° C. was added 4A powdered molecular sieves and sodiumtriacetoxyborohydride. 1-(4-Cyanobenzyl)-5-imidazole-carboxaldehyde wasadded, followed by 5 drops of acetic acid. The cooling bath was removedafter 5 hours, and the reaction was stirred for another 15 hours. Thereaction was poured into ethyl acetate and water. The organic layer wasextracted with sat. aq. NaHCO₃ solution and brine, then dried (Na₂ SO₄)and concentrated in vacuo to provide the product.

Analysis calculated for C₂₅ H₂₂ N₄ O: C, 73,38; H, 6.07; N, 12.53;Found: C, 73.36; H, 6.00; N, 12.49.

Example 32 1-(3'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 3-iodotoluene.

Anal. Calcd. for C₂₅ H₂₁ N₃.1.00 HCl.0.45 H₂ O: C, 73.75; H, 5.64; N,10.32. Found: C, 73.69; H, 5.40; N, 10.39. FABMS 364 (MH⁺).

Example 33 1-(4'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 4-iodotoluene.

Anal. Calcd. for C₂₅ H₂₁ N₃ ·1.00 HCl·0.10 H₂ O: C, 74.75; H, 5.57; N,10.46. Found: C, 74.79; H, 5.37; N, 10.09. FABMS 364 (MH⁺).

Example 34 1-(3'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)idazole hydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 3-trifluoomethyl iodobenzene.

FABMS 418 (MH⁺).

Example 35 1-(4'-Trifluoromethyl-4-biphenylmethyl)-5-(4-csyanobenzyl)imidazole hydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 4-trifluoromethyl iodobenzene.

Anal. Calcd. for C₂₅ H₁₈ N₃ F₃ ·0.95 HCl·1.15 H₂ O: C, 58.97; H, 4.40;N, 8.25. Found: C, 58.92; H, 4.40; N, 8.43. FABMS 418 (MH⁺).

Example 36 1-(3'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 3-chloroiodobenzene.

Anal. Calcd. for C₂₅ H₂₁ N₃ ·1.00 HCl·0.25 H₂ O: C, 68.00; H, 4.61; N,9.91. Found: C, 67.95; H, 4.57; N, 10.30; FABMS 384 (MH⁺).

Example 37 1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 4-chloroiodobenzene.

Anal. Calcd. for C₂₅ H₂₁ N₃ ·1.00 HCl·0.90 H₂ O: C, 66.03; H, 4.80; N,9.63. Found: C, 66.09; H, 4.75; N, 9.48; FABMS 384 (MH⁺).

Example 38 1-(2'3'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazoehydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 2,3-dichloroiodobenzene.

FABMS 418 (MH⁺).

Example 39 1-(2'4'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 2,4-dichloroiodobenzene.

Anal. Calcd. for C₂₄ Hl₇ N₃ Cl₂ ·1.00 HCl·0.30 H₂ O: C, 62.64; H, 4.07;N, 9.13. Found: C, 62.64; H, 4.23; N, 8.86; FABMS 418 (MH⁺).

Example 40 1-(2'5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example5, steps A-C using 2,5-dichloroiodobenzene.

Anal. Calcd. for C₂₄ H₁₇ N₃ Cl₂ ·1.20 HCl·0.35 H₂ O: C, 61.55; H, 4.07;N, 8.97; Found: C, 61.53; H, 4.08; N, 9.03; FABMS 418 (MH⁺).

Example 41 1-(3'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrobromide salt

The title compound was prepared using the protocol described in Example13, steps A-C using 3-trifluoro iodobenzene.

Anal. Calcd. for C₂₅ H₁₈ N₃ OF₃ ·1.00 HCl.: C, 63.91; H, 4.08; N, 8.94;Found: C, 63.77; H, 3.97; N, 8.60; FAB HRMS exact mass calcd for C₂₅ H₁₈N₃ OF₃ 434.147543 (MH⁺); found 434.148022.

Example 42 1-(2'-Fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrobromide salt

The title compound was prepared using the protocol described in Example13, steps A-C using 2-fluoro iodobenzene.

Anal. Calcd. for C₂₄ H₁₈ N₃ F.1.20 HBr.0.15 H₂ O: C, 63.91; H, 4.31; N,9.32; Found: C, 64.04; H, 4.12; N, 8.92; FABMS 368 (MH⁺).

Example 431-(4-(2'-Trifluoromethylphenyl)-2-Chlorophenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example13, steps A-C using 2-chloro-4-iodotoluene and 2-trifluoromethylbenzeneboronic acid.

Anal. Calcd. for C₂₅ H₁₇ N₃ F₃ Cl.1.00 HCl.0.15 EtoAc: C, 61.31; H,3.86; N, 8.38; Found: C, 61.33; H, 3.78; N, 8.15; FABMS 452 (MH⁺).

Example 441-{1-(4-(2'-trifluoromethylphenyl)phenyl)ethyl}-5-(4-cyanobenzyl)imidazole hydrochloride salt

Step A: 4-(2'-trifluoromethylphenyl)benzaldehyde

To a solution of 4-formylbenzeneboronic acid (4.00 g, 26.7 mmol) and Na₂CO₃ (5.66 g, 53.4 mmol) in water (240 mL) was added p-dioxane (240 mL).This mixture was treated sequentially with 2-iodobenzotrifluoride (3.74mL, 26.7 mmol) and palladium (II) acetate (540 mg, 2.40 mmol) andallowed to stir at ambient temperature for 24 hours. The solvent wasevaporated in vacuo. To the residue was added EtOAc (400 inL) and water(300 mL). The aqueous layer was acidified to pH 2 with 1.0 N aq. HCl andthe layers separated. The aqueous layer was extracted with EtOAc (2×200mL). The organic extracts were combined, washed with brine (200 mL), 5%aq. Na₂ S₂ O₃ (200 mL), saturated NaCl (200 mL), dried (Na₂ SO₄), andthe solvent evaporated in vacuo and the residue chromatographed (Silicagel, 20-50% CH₂ Cl₂ in hexanes) to afford the title compound.

¹ H NMR (CDCl₃, 400 MHz) δ 10.09(1H, s), 7.93(2H, d, J=8.0 Hz), 7.78(1H,d, J=8.2 Hz), 7.60(1H, t, J=7.5 Hz), 7.55-7.45(3H, m) and 7.33(1H, d,J=8.0 Hz) ppm.

Step B: 1-(4-(2'-trifluoromethylphenyl)phenyl)ethanol

To a solution of 4-(2-trifluoromethylphenyl)-benzaldehyde (1.00 g, 0.40mmol) in Et₂ O (20 mL) at -70° C. was added methyl lithium (2.85 mL of a1.4 M in Et₂ O 0.40 mmol) over 10 minutes. The reaction was allowed towarm to ambient temperature and stirred for 1 hour. The reaction wasquenched by dropwise addition of sat. aq. NH₄ OH and extracted with Et₂O. The organic layer was washed with brine and dried(MgSO₄), and thesolvent evaporated in vacuo. The residue was chromatographed (Silicagel, 20-50% CH₂ Cl₂ in hexanes) to afford the title compound.

¹ H NMR (CDCl₃, 400 MHz) δ 7.75(1H, d, J=7.7 Hz), ), 7.55(1H, t, J=7.4Hz), 7.47(1H, t, J=7.4 Hz), 7.41(2H, d, J=7.9 Hz), 7.36-7.28(3H, m) and4.98(1H, m) ppm.

Step C:1-{1-(4-(2'-trifluoromethylphenyl)phenyl)ethyl}-5-(4-cyanobenzyl)imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example5, step C using the alcohol from step B.

Anal. Calcd. for C₂₆ H₂₀ N₃ F₃.1.00 HCl.1.1 EtOAc: C, 66.52; H, 4.61; N,8.81. Found: C, 66.74; H, 4.52; N, 8.98.

Example 45 1-(2'-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl)imidazole

Step A: E-Ethyl-3-(4-(2'-trifluoromethylphenyl)phenyl)prop-2-enoate

To a solution of 4-(2'-trifluoromethylphenyl) benzaldehyde (1.00 g,3.996 mmol, prepared using the protocol described in Example 44, step A)in CH₂ Cl₂ (8.0 mL) was added (carbethoxymethylene) triphenylphosphorane(1.46 g, 4.196 mmol)and the reaction was stirred at room temperature for16 hours. The solvent was evaporated in vacuo and the residuechromatographed (Silica gel, 2.5% EtOAc in hexanes) to afford the titlecompound.

¹ HNMR (CD₃ OD 400 MHz) δ 7.90-7.50(6H,m),), 7.40 7.35(3H,m), 6.60(1H,d,J=16.1 Hz), 4.27(2H, q, J=7.1 Hz), 1.34(3H, t, J=7.1 Hz),)ppm.

Step B: Ethyl-3-(4-(2'-trifluoromethylphenyl)phenyl)-propionoate

A solution of E-Ethyl-3-(4-(2'-trifluoromethylphenyl)phenyl)prop-2-enoate (0.444 g, 1.388 mmol) and 10% palladium on carbon(0.044 g) in ETOH (13.88 mL) was hydrogenated in a parr apparatus. Thecatalyst was removed by filtration through celite and the title compoundobtained by solvent evaporation in vacuo.

¹ H NMR (CD₃ OD 400 MHz) δ 7.73(1H, d, J=7.7 Hz), 7.58(1H, t, J=7.7 Hz),7.48(1H, t, J=7.7 Hz), 7.29(1H, d, J=7.7 Hz), 7.24 (2H, d, J=8.2 Hz),7.19(2H, d, J=8.2 Hz), 4.10(2H, q, J=7.1 Hz), 2.96(2H, t, J=7.7 Hz),2.65(2H, t, J=7.5 Hz) and 1.20(2H, qn, J=7.5 Hz) ppm.

Step C:1-(2'-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl)imidazole

The title compound was prepared using the protocol described in Example5, steps B-C using the product from step B.

¹ H NMR (CD₃ OD 400 MHz) δ 7.75(1H, d, J=7.7 Hz), 7.70-7.60(3H, m),7.52(1H, t, J=7.5 Hz), 7.33(1H, d, J=7.9 Hz), 7.21 (1H, d, J=7.6 Hz),7.13 (2H, d, J=8.1 Hz), 6.78(1H, s), 4.03(2H, q, J=7.1 Hz), 3.86 (2H, t,J=7.5 Hz), 2.60(2H, t, J=7.5 Hz) and 1.92(2H, qn, J=7.5 Hz) ppm.

Example 461-(2'-N-t-Butoxycarbonylamino-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

Step A: 4-(2'-Cyanophenyl)benzoic acid methyl ester.

To a solution of 2-bromobenzonitrile (1.00 g, 5.494 mmol), in THF (16.5mL) at -100° C. was added t-butyl lithium (6.46 mL, of a 1.7M solutionin pentane, 10.98 mmol. After 5 minutes zinc chloride(5.494 mL, of a 1Msolution in THF, 5.494 mmol) was added. The reaction was stirred for 10minutes at -78° C. and then allowed to warm to 0° C. and stirred for 1hour. This solution was added via cannula to a solution ofmethyl-4-iodobenzoate (1.44 g, 5.494 mmol) and bis(triphenylphosphine)Nickel II chloride (0.359 g, 0.549 mmol) in THF (12 mL). The reactionstirred for 1 hour at 0° C. and then at ambient temperature for afurther 16 hours. Saturated ammonium hydroxide solution (5 mL) was addedand the mixture stirred until homogenous, extracted with EtOAc and theorganic extracts washed with saturated brine, dried (MgSO₄) andevaporated in vacuo. The residue was chromatographed (Silica gel, 50%CH₂ Cl₂ to 50%) EtOAc in hexanes) to afford the title compound.

¹ H NMR (CD₃ OD, 400 MHz) δ 8.15(2H, d, J=8.7 Hz), ),7.87(1H, d, J=7.7Hz), 7.77(1H, t, J=7.5 Hz),), 7.69(2H, d, J=8.7 Hz), 7.65-7.55(2H, m),and 3.95(3H, s) ppm.

Step B: 4-(2'-Aminomethylphenyl)hydroxymethylbenzene

To a solution of 4-(2'-cyanophenyl)benzoic acid methyl ester (0.428 g,1.804 mmol) in tetrahydrofuran (14.3 mL) at 0° C. was added 1.0 Mlithium aluminum hydride in tetrahydrofuran (3.61 mL, 3.61 mmol) over 10minutes. The reaction was allowed to stir at ambient temperature for 3hours, then warmed to 45° C. for 3 hours, cooled and quenched bydropwise addition of saturated Na₂ SO₄ (0.46 mL). The reaction wasdiluted with diethylether, Na₂ SO₄ was added, the mixture filteredthrough a pad of Celite and the filtrate evaporated in vacuo to affordthe title compound.

¹ H NMR (CD₃ OD, 400 MHz) δ 7.47(1H, d, J=7.5 Hz), 7.42(2H, d, J=8.4Hz), 7.40-7.15 (4H,m), 4.66(2H,s) and 3.73(2H,s) ppm.

Step C: 4-(2'-t-Butoxycarbonylaminomethylphenyl) hydroxymethylbenzene

To a solution of 4-(2'-aminomethylphenyl) hydroxymethylbenzene (0.374 g,1.754 mmol) and triethylamine (0.269 mL, 1.929 mmol) in DMF (8.0 mL) at0° C. was added 1-butylcarbonate (0.383 g, 1.754 mmol) in DMF (2.0 mL)over 10 minutes. The reaction was allowed to stir at ambient temperaturefor 16 hours. The reaction was diluted with EtOAc, washed with 10% aq.citric acid, and then sat. aq. NaHCO₃ and dried(Na₂ SO₄). The solventwas evaporated in vacuo and the residue chromatographed (Silica gel,EtOAc) to afford the title compound.

¹ H NMR (CD₃ OD, 400 MHz) δ 7.50-7.15(1H, m), 4.66(2H,s), 4.15(2H,s) and1.43(9H,s) ppm

Step D:1-(2'-N-t-Butoxycarbonylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

The title compound was prepared using the protocol described in Example5, step C using the product from step C.

FAB HRMS exact mass calcd for C₃₀ H₃₀ N₄ O₂ 479.244702 (MH⁺); found479.244189. Anal. Calcd. for C₃₀ H₃₀ N₄ O₂.0.10 H₂ O: C, 75.29; H, 6.32;N, 11.71. Found: C, 75.20; H, 5.87; N, 11.27.

Example 471-(2'-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

A solution of1-(2'-N-t-Butoxycarbonylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole(43.7 mg, 0.094 mmol) in EtOAc (10 mL) was saturated with HCl gas. After10 minutes the solvent was evaporated in vacuo to afford the titlecompound as a white solid.

FAB HRMS exact mass calcd for C₂₅ H₂₂ N₄ 379.192272 (MH⁺); found379.192525. Anal. Calcd. for C₂₅ H₂₂ N₄.0.75 HCl: C, 62.71; H, 5.21; N,11.70. Found: C, 62.71; H, 5.14; N, 11.32.

Example 48 1-(2'-Acetylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

To a solution of1-(2'-aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehyrochloride (0.107 g, 0.237 mmol) and triethylamine (0.033 mL, 0.237mmol) in CH₂ Cl₂ (4.7 mL) at 0° C. was added acetic anhydride (0.383 g,1.754 mmol). The reaction was allowed to stir at ambient temperature for16 hours. The reaction was diluted with CH₂ Cl₂, washed sat. aq. Na₂ CO₃and dried (Na₂ SO₄). The solvent was evaporated in vacuo and the residuechromatographed (Silica gel, 3% MeOH in CH₂ Cl₂) to afford the free basewhich was converted to the HCl salt.

FAB HRMS exact mass calcd for C₂₅ H₂₂ N₄ O 421.202837 (MH⁺); found421.203621. Anal. Calcd. for C₂₅ H₂₂ N₄ O 1.60 HCl: C, 67.72; H, 5.39;N, 11.70. Found: C, 67.58; H, 5.21; N, 11.77.

Example 491-(2'-Methylsulfonylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride

The title compound was prepared using the protocol described in Example48, using methanesulfonyl chloride.

FAB HRMS exact mass calcd for C₂₆ H₂₄ N₄ O₂ S 457.169823 (MH⁺); found457.170937. Anal. Calcd. for C₂₆ H₂₄ N₄ O₂ S 1.70 HCl 0.20 EtOAc: C,60.03; H, 5.13; N, 10.45. Found: C, 59.99; H, 4.93; N, 10.05.

Example 49 1-(2'-Ethylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride

To a solution of1-(2'-aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehyrochloride (0.100 g, 0.222 mmol) acetaldehyde (0.024 mL, 0.444 mmol)and 4A molecular sieves (300 mg) in MeOH (0.44 mL) at room temperaturewas added triethylamine to a pH of 7. Sodium cyanoborohydride (0.028 g,0.444 mmol) was added and the reaction was stirred for 16 hours. Thereaction was filtered through celite and the filtrate evaporated invacuo. The residue was partitioned between CH₂ Cl₂, and sat. aq. Na₂ CO₃and the organic layer separated and dried (Na₂ SO₄). The solvent wasevaporated in vacuo and the residue chromatographed (Silica gel, 3% NH₄OH in Acetonitrile) to afford the free base which was converted to theHCl salt.

FAB HRMS exact mass calcd for C₂₇ H₂₆ N₄ 407.223572 (MH⁺); found421.223572.

Example 50 1-(2'-Phenylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride

To a slurry of1-(2'-aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehyrochloride (0.097 g, 0.216 mmol) triphenyl bismuth (0.166 g, 0.377mmol) and copperII a cetate (0.059 g, 0.323 mmol) in CH₂ Cl₂ (0.43 mL)at room temperature was added triethylamine (0.045 mL, 0.323 mmol) andthe reaction was stirred for 16 hours. Silica gel was added and thesolvent evaporated in vacuo. The solid was applied to a column andchromatographed (Silica gel, 2% MeOH in CH₂ Cl₂) to afford the free basewhich was converted to the HCl salt.

FAB HRMS exact mass calcd for C₃₁ H₂₆ N₄ 454.215747 (MH⁺); found454212863.

Example 51 1-(2'-Glycinylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride

To a slurry of1-(2'-aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehyrochloride (0.0100 g, 0.222 mmol) N-Boc glycine (0.039 g, 0.222 mmol),triethylamine (0.093 mL, 0.666 mmol) and HOBT (0.030 g, 0.222 mmol) inCH₂ Cl₂ (2.2 mL) at room temperature was added EDC (0.042 g, 0.222 mmol)and the reaction was stirred for 16 hours. The reaction was diluted withCH₂ Cl₂ and washed with NaHCO₃ and the organic extracts dried (Na₂ SO₄)and evaporated in vacuo. The residue was chromatographed (Silica gel,2.5-5% MeOH in CH₂ Cl₂) to afford the N-Boc glycinyl derivative. Thismaterial was dissolved in EtOAc (3 mL) and saturated with HCl gas. Thereaction was stirred for 40 minutes at 0° C. and the solvent evaporatedto afford the title compound as a white solid

FABMS 436(MH⁺); C₂₇ H₂₅ N₅ O; Anal. Calcd. for C₂₇ H₂₅ N₅ O 1.55 HCl2.70 H₂ O: C, 60.06; H, 5.96; N, 12.97. Found: C, 60.04; H, 5.96; N,12.93.

Example 52 1-(2'-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl)imidazole and 1-(2'-Methyl-4-biphenylmethyl)-4-chloro5-(4-cyanobenzyl)imidazole

A solution of 1-(4-(4'-Methylbiphenylmethyl)-5-(4-cyanobenzyl)imidazole(120 mg, 0.330 mmol) in CH₂ Cl₂ was treated with NCS (44 mg, 0.330 mmol)and the reaction stirred for 16 hours at room temperature. The solventwas evaporated in vacuo and the residue chromatographed (Silica gel, 2%MeOH in CH₂ Cl₂) to afford a mixture of regioisomers. These wereseparated by preparative HPLC to afford the title compounds.

1-(2'-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl) imidazole;

¹ H NMR (CD₃ OD, 400 MHz) δ 7.54(1H, d, J=8.2 Hz), 7.27(2H, d, J=8.4Hz), 7.25-7.10 (7H, m), 6.93(2H, d, J=8.4 Hz), 6.85(1H, s), 5.21(2H, s),4.05(2H, s) and 2.20(3H, s)ppm.

1-(2'-Methyl-4-biphenylmethyl)-4-chloro 5-(4-cyanobenzyl) imidazole;

¹ H NMR (CD₃ OD, 400 MHz) δ 7.79(1H, s), 7.50(1H, d, J=8.2 Hz),7.25-7.02 (9H, m), 7.00(2H, d, J=8.4 Hz), 5.15(2H, s), 4.05(2H, s) and2.16(3H, s)ppm.

Example 531-(3'-Chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)-imidazolehydrochloride salt

Step A: Preparation of4-trifluoromethylsulfonylyoxy-3-methylbenzaldehyde

To a solution of 4-hydroxy-3-methylbenzaldehyde (Aldrich; (1 g; 7.34mmol) in 20 mL of CH₂ Cl₂ at room temperature was added triethylamine(1.13 mL, 8.08 mmol), then triflic anhydride (1.36 mL, 8.08 mmol). After2 h, the reaction was poured into CH₂ Cl₂, washed with saturated NaHCO₃,then brine, dried, filtered, and concentrated in vacuo to provide thecrude aldehyde. Column chromatography (silica gel; hexane:EtOAc 4:1)afforded the title compound as an oil.

Step B: Preparation of (3'-chlorophenyl)-3-methylbenzaldehyde

Following the procedure described for Example 13, step A, but using theproduct from step A above and 3-chlorobenzeneboronic acid as startingmaterials the title product was obtained.

Step C: Preparation of (3'-chlorophenyl)-3-methylbenzylalcohol

Following the procedure described for Example 7, step B, but using theproduct from step B above as starting material, the title product wasobtained.

Step D: Preparation of1-(3'-chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazolehydrochloride salt

Using the alcohol from step C and following the procedure described forExample 5, step C with a subsequent purification by silica gelchromatography (EtOAc then 2% MeOH in CHCl₃). The first eluted materialafforded the title compound after treatment with HCl and Et₂ O.

Analysis calculated for C₂₅ H₂₀ ON₃ Cl•2.7HCl•0.3Et₂ O: C, 60.67; H,4.99; N, 8.10; Found: C, 60.67; H, 4.62; N, 7.95.

Example 541-(3'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Following the procedure of Example 53, step D, but collecting the latereluting material the title compound was obtained.

Analysis calculated for C₂₅ H₂₀ N₃ Cl•1.7HCl•0.2Et₂ O: C, 65.27; H,5.03; N, 8.85; Found: C, 65.36; H, 5.03; N, 8.86.

Example 551-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazolehydrochloride salt

Following the procedure described for Example 53, steps B-C but using3-trifluoromethylbenzeneboronic acid as starting materials, the titlecompound was obtained. It was isolated by silica gel chromatography(EtOAc then 2% MeOH in CHCl₃) collecting the first eluted material andthen subsequent treatment with HCl and Et₂ O.

Analysis calculated for C₂₆ H₂₀ N₃ F₃ •1.4HCl•0.35 EtOAc: C, 64.10; H,4.75; N, 8.18; Found: C, 64.14; H, 4.50; N, 8.10.

Example 561-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazoletrifluoroacetic acid salt

Following the procedure described for Example 53, steps B-C but using3-trifluoromethylbenzeneboronic acid as starting materials, the titlecompound was obtained. It was isolated by silica gel chromatography(EtOAc then 2% MeOH in CHCl₃) collecting the second eluted material andthen subsequent preparative HPLC purification.

Analysis calculated for C₂₆ H₂₀ N₃ F₃ •1.35TFA•0.4H₂ O: C, 58.17; H,3.77; N, 7.09; Found: C, 58.17; H, 3.78; N, 7.19.

Example 571-(3'-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Step A: Preparation of 2-bromo-5-hydroxylmethyltoluene

To a solution of 4-bromo-3-methyltenzoic acid (Aldrich; (3 g, 14 mmol)in 75 mL of THF at 0° C. was added BH₃.THF complex (1M in THF; 15 mL, 15mmol). After stirring for 3 h at room temperature, 10 mL 1N NaOH wasadded slowly. The solution was poured into water and extracted withCHCl₃, washed with water then brine, dried and evaporated. Columnchromatography of the product (silica gel; EtOAc) afforded the titlecompound as a solid.

Step B: Preparation of 4-(3'-methoxyphenyl)-3-methyl-benzylalcohol

Following the procedure described for Example 13, step A, but using theproduct from step A above and 3-methoxybenzene-boronic acid as startingmaterials the title product was obtained.

Step C: Preparation of1-(3'-methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Following the procedure described for Example 5, step C, but using theproduct from step B above as starting material, the title product wasobtained.

Analysis calculated for C₂₆ H₂₃ N₃)•1.2HCl: C, 71.41; H, 5.58; N, 9.61;Found: C, 71.34; H, 5.45; N, 9.83.

Example 581-(2'-Chloro-4'-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Step A: Preparation of1-chloro-5-fluoro-2-trifluoromethyl-sulfonylyoxybenzene

Following the procedure described for Example A, step A, but using2-chloro-4-fluorophenol as starting materials the title product wasobtained.

Step B: Preparation of1-(2'-Chloro-4'-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Following the procedure described for Example 5, steps A-C, but usingthe product from step A above as; starting material, the title productwas obtained.

Analysis calculated for C₂₄ H₁₇ N₃ OClF•1.1HCl: C, 65.22; H, 4.13; N,9.51; Found: C, 65.33; H, 4.27; N, 9.24.

Example 59 1-(2'-Ethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazoletrifluoroacetic acid salt

Following the procedure described for Example 5, steps A-C, but using1-iodo-2-ethylbenzene as starting material, the title product wasobtained.

Analysis calculated for C₂₆ H₂₃ N₃ •1.35TFA•1.4H₂ O: C, 61.93; H, 4.92;N, 7.55; Found: C, 61.96; H, 5.12; N, 7.16.

Example 60 1-(2'-(2-Propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazoletrifluoroacetic acid salt

Following the procedure described for Example 5, steps A-C, but using1-iodo-2-(2-propyl)benzene as starting material, the title product wasobtained.

Analysis calculated for C₂₇ H₂₅ N₃ •1.5TFA•0.75H₂ O: C, 62.55; H, 4.90;N, 7.29; Found: C, 62.56; H, 4.95; N, 6.98.

Example 611-(2'-(2-Methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Step A: Preparation of2-(2-methyl-2-propyl)-1-trifluoromethyl-sulfonyloxybenzene

Following the procedure described for Example 53, step A, but using2-(2-methyl-2-propyl)phenol as starting materials the title product wasobtained.

Step B: Preparation of1-(2'-(2-methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Following the procedure described for Example 5, steps A-C, but usingthe product from step A above as starting material, the title productwas obtained.

Analysis calculated for C₂₈ H₂₇ N₃ •1.75HCl: C, 71.64; H, 6.17; N, 8.95;Found: C, 71.71; H, 5.93; N, 8.56.

Example 621-(2'-Ethyl-4-biphenylmethy)-5-(4-(1H-tetrazol-5-yl))benzyl)imidazoletrifluoroacetic acid salt

1-(2'-Ethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole (from Example59; 150 mg, 0.4 mmol) was dissolved in toluene (10 mL) and treated withtrimethylsilylazide (0.15 mL, 1.08 mmol) and dibutyltin oxide (110 mg,0.44 mmol). The mixture was heated at 100° C. for 16 h, cooled and thesolvent removed in vacuo. Chromatography of the residue (silica gel;EtOH: NH₄ OH: H₂ O 20:1:1) gave an oil which was further purified bypreparative HPLC to give the title compound.

FAB mass spectrum (M+H)=421.08; Analysis calculated for C₂₆ H₂₄ N₆•1.35TFA•0.15H₂ O: C, 59.72; H, 4.48; N, 14.56; Found: C, 59.71; H,4.42; N, 14.54.

Example 631-[1-(4-Cyanobenzyl)imidazol-5-ylmethoxy]-4-(2'-methylphenyl)-2-(3-N-phthalimido-1-propyl)benzenetrifluoroacetic acid salt

Step A: Preparation of 4-(2'-methylphenyl)phenol

Following the procedure described for Example 5, step A, but4-bromophenol 2-methylbenzeneboronic acid as starting materials thetitle product was obtained

Step B: Preparation of 1-allyloxy-4-(2'-methylphenyl)benzene

The phenol from step A (1.72 g, 9.35 mmol), CS₂ CO₃ (3.6 g, 10.5 mmol)and allylbromide (0.9 mL, 10.3 mmol) in DMF (47 nmL) were stirred atroom temperature for 48 h. The mixture was poured into water andextracted with EtOAc, washed with water (3×), brine, dried andevaporated to give the title compound as an oil.

Step C: Preparation of 2-allyl-4-(2-methylphenyl)phenol

To a stirred solution of BCl₃ (1M in p-xylene; 6.7 mL, 6.7 mmol) inchlorobenzene at -15° C. was added the allyl ether from step B (1.48 g,6.6 mmol) in 5 mL of chlorobenzene. After 1 h at -15° C., the mixturewas poured into ice/MeOH, extracted with Et₂ O (3×), washed withsaturated NaHCO₃, water then brine. The dried solution was evaporated togive the title compound as an oil.

Step D: Preparation of 2-allyl-1-benzyloxy-4-(2-methylphenyl)benzene

Following the procedure of step B but using benzyl bromide, the phenolfrom step C was converted into the title compound

Step E: Preparation of1-benzyloxy-2-(3-hidroxypropyl)-4-(2'-methylphenyl)benzene

To a stirred solution of the allyl derivative from step D, (3.2 g, 10.2mmol) in THF (40 mL) at 0° C. was added 9-BBN (0.5 M in THF; 30.6 mL, 15mmol) and the mixture stirred for 4 h. The solution was treated with 30%H₂ O₂ /1N NaOH and after 15 minutes, poured into water and extractedwith EtOAc (2×). The organic layers were washed with water, brine, driedand evaporated to give an oil. Chromatography on silica gel(hexane/EtOAc 4:1) afforded the title compound as an oil.

Step F: Preparation of1-benzyloxy-2-(3-N-phthalimido-1-propyl)-4-(2'-methylphenyl)benzene

To a stirred solution of the alcohol from step E, (1.5 g, 4.52 mmol) andtriphenylphosphine (1.78 g, 5.65 mmol) in THF (30 mL) at roomtemperature was added dropwise a solution of DEAD (0.9 mL, 5.65 mmol)and phthalimide (731 mg, 5 mmol) in THF (5 mL). After stirring for 16 h,the mixture was concentrated in vacuo and the residue taken up in EtOAc.The solution was washed with 10% citric acid solution, saturated NaHCO₃,water then brine, dried and evaporated to give an oil. Columnchromatography (silica gel; hexane:EtOAc 9:1) afforded the titlecompound as an oil.

Step G: Preparation of2-(3-N-phthalimido-1-propyl)-4-(2'-methylphenyl)phenol

To a degassed solution of the benzylether from step F, (1.5 g, 3.3 mmol)in EtOH (30 mL) and EtOAc (5 mL) was added 300 μL of HOAc and 10%palladium hydroxide on carbon (150 mg) and this was then placed on aParr hydrogenation apparatus at 50 psi of hydrogen. After shaking for 24h, the mixture was filtered through celite, the solvent removed and theresidue chromatographed (silica gel; hexane:EtOAc 3:1) to give the titlecompound as an oil.

Step H: Preparation of 1-(4-cyanobenzyl)-5-chloromethylimidazolehydrochloride

A suspension of 1-(4-cyanobenzyl)-5-hydroxymethylimidazole (Example 26,step D; 3.1 g, 14.5 mmol) in thionyl chloride (20 mL) was heated at 60°C. for 18 h. The excess thionyl chloride was removed in vacuo and theresidue was azeotroped with CHCl₃ (3×) to give the title compound.

Step I: Preparation of1-[1-(4-cyanobenzyl)imidazol-5-ylmethoxy]-4-(2'-methylphenyl)-2-(3-N-phthaliniido-1-propyl)benzenetrifluoroacetic acid salt

Following the procedure described for step B, but using the phenol fromstep G and 5-chloromethyl-1-(4-cyanobenzyl) imidazole hydrochloride fromstep H as starting materials, the title compound was obtained.

FAB mass spectrum (M+H)=567.10. Analysis calculated for C₃₆ H₃₀ N₄ O₃•1.5TFA•1.0H₂ O: C, 61.98; H, 4.47; N, 7.41; Found: C, 61.91; H, 4.46;N, 7.31.

Example 641-(3',5'-Ditrifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Following the procedure described for Example 5, steps A-C, but using4-bromo-3-methylbenzoic acid and 3,5-ditrifluoromethylbenzeneboronicacid as starting materials, the title product was obtained.

Analysis calculated for C₂₇ H₁₉ N₃ •1.0HCl•0.25H₂ O: C, 60.00; H, 3.82;N, 7.78; Found: C, 59.91; H, 3.74; N, 7.75.

Example 651-(3',5'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Following the procedure described for Example 5, steps A-C, but using4-bromo-3-methylbenzoic acid and 3,5-dichlorobenzeneboronic acid asstarting materials, the title product was obtained.

Analysis calculated for C₂₅ H₁₉ N₃ Cl₂ •1.0HCl•1.5H₂ O: C, 60.56; H,4.68; N, 8.47; Found: C, 60.40; H, 4.83; N, 8.23.

Example 661-(3',5'-Dimethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Following the procedure described for Example 5, steps A-C, but using4-bromo-3-methylbenzoic acid and 3,5-dimethylbenzeneboronic acid asstarting materials, the title product was obtained.

Analysis calculated for C₂₇ H₂₅ N₃ •1.0HCl: C, 75.77; H, 6.12; N, 9.82;Found: C, 75.66; H, 6.10; N, 9.71.

Example 671-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole

Step A: Preparation of 4-hydroxymethyl-biphenyl-3-carbaldehyde

To a solution of 4-biphenylmethanol (0.368 g, 2 mmol) in ether (25 mL)and TMEDA (1.21 mL, 8 mmol), at 0° C. was added n-butyllithium (2.5Nhexanes; 3.2 mL, 8 mmol). The solution was then heated at reflux for 1h, cooled to -60° C. and CuCN (0.2 g, 2.2 mmol) added. After 30 minutes,the solution was cooled to -78° C. and N-formylpiperidine (1.11 mL, 10mmol) was then added dropwise and stirring was continued for 1 h. Themixture was then warmed to -10° C., quenched with saturated NH₄ Cl,extracted with ether washed with brine, dried and the solvent removed invacuo. Chromatography of the residue (silica gel; hexane:EtOAc 4:1)afforded the title compound as a colorless oil.

Step B: Preparation of 4-hydroxymethyl-biphenyl-3-carbaldehydeO-methyl-oxime

A solution of the aldehyde from step A (0.13 g, 0.61 mmol),methoxylamine hydrochloride (61 mg, 0.735 mmol) and pyridine (2 mL) inEtOH (10 mL) was heated at reflux for 16 h. Further portions ofmethoxylamine hydrochloride (61 mg, 0.735 mmol) and pyridine (2 mL) wereadded and heating was continued for 24 h. The solution was cooled,diluted with EtOAc, extracted with water (2×) then brine, dried andconcentrated to give the title compound as an oil. This was used as suchin the next step.

Step C: Preparation of 3-aminomethyl-biphenyl-4-methanol

To a solution of the oxime from step B (0.51 g, 2.1 mmol) in THF (15 mL)at 0° C. was added BH₃.THF (1M in hexane; 8 mL, 8 mmol) and theresulting solution was stirred at room temperature for 16 h then heatedto reflux for 24 h. The solution was cooled to 0° C. and 1N NaOH (10 mL)was added slowly. After 1 h, the mixture was diluted with water,extracted with EtOAc (3×), washed with brine, dried and evaporated togive the title compound as an oil. This was used as such in the nextstep.

Step D: Preparation of 3-N-Boc-aminomethyl-biphenyl-4-methanol

To a solution of the amine from step C (0.39 g, 1.8 mmol) and Et₃ N(0.255 mL, 1.8 mmol) in DMF (10 mL) was added Boc-anhydride (0.4 g, 1.8mmol) and the mixture was stirred for 16 h. The solution was dilutedwith water, extracted with EtOAc (3×) and the combined organic layerswere then extracted with saturated NaHCO₃ then brine, dried andevaporated. Chromatography of the residue (silica gel; hexane:EtOAc 3:1)afforded the title compound as a solid.

Step F: Preparation of 3-(N-Boc-aminomethyl)-4-biphenylmethyl bromide

A solution of the alcohol from step D (0.157 g, 0.5 mmol),triphenylphosphine (0.191 g, 0.75 mmol,) and CBr₄ (0.249 g, 0.75 mmol)in THF (15 mL) was stirred at room temperature for 16 h. The solvent wasremoved in vacuo and EtOAc was added to the residue. Filtration removedthe insoluble material and the EtOAc solution was washed with water thenbrine, dried and evaporated. Purification of the residue on silica gel,eluting with hexane:EtOAc 12:1, afforded the title compound.

Step G: Preparation1-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole

Following the procedure of Example 1, step B but using the bromide fromstep G as starting material, the title compound was obtained as a solid.

Fab mass spectrum (M+H)=479.12; Analysis calculated for C₃₀ H₃₀ N₄ O₂•0.05CHCl₃ : C, 74.41; H, 5.67; N, 11.38; Found: C, 74.48; H, 6.25; N,11.56.

Example 68 1-(3-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazoledihydrochloride salt

1-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazolefrom Example 67 was dissolved in EtOAc 0° C. and treated with HCl gas.The solvent was removed to give the title compound.

Fab mass spectrum (M+H)=379.16.

Example 691-(4-Cyanobenzyl)-2-methyl-5-(2'-methylbiphenyl-4-yloxy)imidazoletrifluoroacetate salt

Step A: Methyl N-(cyanomethyl)ethanimidate

Finely grounded aminoacetonitrile hydrochloride (21 g) was stirred in asolution of chloroform (200 mL) saturated with ammonia gas for 10-15minutes. The slurry was filtered through a plug of Celite. The filtratewas concentrated, and the residue distilled (36-40° C., 0.1 mmHg) toprovide aminoacetonitrile as clear, colorless oil. Aminoacetonitrile (14g) was added at a rate of I mL/min to a boiling mixture of trimethylorthoacetate (200 mL), concentrated sulfuric acid (5 drops), andanhydrous sodium sulfate (20 g), with removal of distillate. Theresultant mixture was heated for additional 30 minutes, filtered throughCelite, and concentrated. The residue was distilled (50-60° C., 0.1mmHg) to provide methyl N-(cyanomethyl)ethanimidate as clear, colorlessoil. The ethanimidate was stored under dry argon at -10° C.

¹ H NMR (CDCl₃ 300 MHz) δ 4.11 (2H, s), 3.66 (3H, s), 1.97 (3H, s) ppm.

Step B: 5-(4-Bromophenyloxy)-2-methylimidazole

Using procedure described for the preparation of5-(4-cyanophenyloxy)imidazole in Example 17, Step A, but substituting4-bromophenol for 4-cyanophenol, methyl N-(cyanomethyl) ethanimidate formethyl N-(cyanomethyl)methanimidate, and after heating the resultantmixture at 100° C. for 4 hours, 5-(4-bromophenyloxy)-2-methylimidazolewas prepared:

¹ H NMR (DMSO-d₆ 300 MHz) δ 7.45 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=8.8Hz), 6.91 (1H, s) and 2.22 (3H, s) ppm.

Step C: 5-(4-Bromophenyloxy)-1-(4-cyanobenzyl)-2-methylimidazole

To a cold (-78° C.) solution of 5-(4-bromophenyloxy)-2-methylimidazole(2.06 g, 8.14 mmol) in THF (30 mL), a solution of MeLi in diethyl ether(1.4 M, 8.96 mmol) was added. The resultant mixture was stirred at -78°C. for 1 hour, and a solution of 4-cyanobenzyl bromide (1.68 g, 8.55mmol) in THF (3 mL) was added. The mixture was allowed to warm up toroom temperature, stirred overnight, and concentrated under vacuum. Theresidue was partitioned between water and a 9:1 mixture of methylenechloride and methanol. The organic extract was washed with brine, dried(anhydrous sodium sulfate), filtered, and concentrated under vacuum. Theresidue was subjected to column chromatography on silica gel elutingwith a mixture of chloroform and acetone (8:2 v/v). Two alkylationproducts were isolated. ¹ H NMR NOE experiments indicated that the majorproduct to be 5-(4-bromophenyloxy)-3-(4-cyanobenzyl)-2-methylimidazole,and the minor product to be desired5-(4-bromophenyl-oxy)-1-(4-cyanobenzyl)-2-methylimidazole.

¹ H NMR (minor isomer; CDCl₃ 300 MHz) δ 7.62 (2H, d, J=8.8 Hz), 7.39(2H, d, J=9.0 Hz), 7.16 (2H, d, J=8.8 Hz), 6.89 (2H, d, J=9.0 Hz), 6.54(1H, s), 4.98 (2H, s), and 2.30 (3H, s) ppm.

Step D:1-(4-Cyanobenzyl)-2-methyl-5-(2'-methylbiphenyl-4-yloxy)-imidazoletrifluoroacetate salt

The title compound was prepared as a white solid using the protocoldescribed in Example 19--Step D, substituting5-(4-bromo-phenyloxy)-1-(4-cyanobenzyl)imidazole with5-(4-bromophenyl-oxy)-1-(4-cyanobenzyl)-2-methylimidazole, phenylboronic acid with o-tolylboronic acid, and stirring the reaction mixtureat 100° C. for 18 hours.

Anal. Calcd for C₂₅ H₂₁ N₃ O•1.10 TFA•0.95 H₂ O: C, 62.59; H, 4.63; N,8.05. Found: C, 62.61; H, 4.66; N, 7.75. ¹ H NMR (CDCl₃ 300 MHz) δ 6.68(1H, s), 5.04 (2H, s), 2.31 (3H, s), and 2.23 (3H, s) ppm.

Example 705-(4-Cyanobenzyl)-1-(3-cyano-2'-trifluoromethylbiphenyl-4-ylmethyl)-imidazolehydrochloride salt

Step A: 3-Cyano-4-methyl-2'-trifluoromethylbiphenyl

The title compound was prepared as a white solid using the protocoldescribed in Example 19--Step D, substituting5-(4-bromophenyloxy)-1-(4-cyanobenzyl)imidazole with2-methyl-5-iodobenzonitrile, phenyl boronic acid witho-trifluoromethylboronic acid, and stirring the reaction mixture at 100°C. for 18 hours.

¹ H NMR (CDCl₃ 300 MHz) δ 7.8-7.2 (7H, m) and 2.61 (3H, s) ppm.

Step B: 4-Bromomethyl-3-cyano-2'-trifluoromethylbiphenyl

A mixture of 3-cyano-4-methyl-2'-trifluoromethylbiphenyl (420 mg, 1.61mmol), N-bromosuccinimide (286 mg, 1.61 mmol), AIBN (10 mg), and carbontetrachloride (20 mL) was refluxed for 1 hour. The resultant mixture wasconcentrated, and the residue subjected to column chromatography onsilica gel eluting with a mixture of ethyl acetate in hexane (7.5 to92.5 v/v). Collection and concentration of appropriate fractionsprovided the title compound.

¹ H NMR (CDCl₃ 300 MHz) δ 7.8-7.2 (7H, m) and 4.69 (2H, s) ppm.

Step C:5-(4-Cyanobenzyl)-1-(3-cyano-2'-trifluoromethylbiphenyl-4-ylmethyl)-imidazolehydrochloride salt

The title compound was prepared as a white solid using the protocoldescribed in Example 1--Step B, substituting 4-chloromethyl-biphenylwith 4-bromomethyl-3-cyano-2'-trifluoromethylbiphenyl.

Anal. Calcd for C₂₆ H₁₇ N₄ F₃ •1.50 HCl•1.45 H₂ O: C, 59.68; H, 4.12; N,10.71. Found: C, 59.74; H, 4.12; N, 10.53.

Example 71 2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-cyanobenzyl)imidazole

Step A: N-Methoxy-N-methyl2-(N-tert-butyloxycarbonylamino)-2-(biphenyl-4-ylmethyl)acetamide

To a cold (0° C.) solution of N-Boc 4-biphenylalanine (2.5 g, 7.33 mmol)and N-methylmorpholine (0.96 mL, 8.79 mmol) in ethyl acetate (20 mL),isobutyl chloroformate (1.04 mL, 8.06 mmol) was added. The resultantmixture was stirred at 0° C. for 30 min. N,N-Dimethyl-hydroxyaminehydrochlori(e (0.86 g, 8.79 mmol) and N-methyl-morpholine (0.96 mL, 8.79mmol) was added, and the resultant mixture was stirred at room temp.overnight. The product mixture was diluted with ethyl acetate (100 mL).The organic extract was washed with brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was subjectedto column chromatography on silica gel eluting with 40% ethyl acetate inhexane. Collection and concentration of appropriate fractions providedthe title compound as white solid.

¹ H NMR (CDCl₃ 300 MHz) δ 7.6-7.2 (9H, m), 5.2 (1H, br s), 5.0 (1H, brs), 3.69 (3H, s), 3.19 (3H, s), 3.0 (2H, m), and 1.39 (9H, s).

Step B: N-Methoxy-N-methyl2-[(N-tert-butyloxycarbonyl)-(N-4-bromobenzyl)amino]-2-(biphenyl-4-ylmethyl)acetamide

To a cold (-78° C.) solution of N-methoxy-N-methyl2-(N-tert-butyloxycarbonylamino)-2-(biphenyl-4-ylmethyl)acetamide (2.25g, 5.86 mmol) in THF (60 mL), a solution of sodiumbis(trimethylsilyl)amide in THF (1 M, 6.44 mL, 6.44 mmol) was added. Theresulting mixture was stirred at -78° C. for 1 hour. A solution of4-bromobenzyl bromide (1.61 g) in THF (5 mL) was added, and theresultant mixture was allowed to warm up to room temp, and stirredovernight. The product mixture was diluted with diethyl ether. Theorganic extract was washed with brine, dried over magnesium sulfate,filtered, and concentrated under vacuum. The residue was subjected tocolumn chromatography on silica gel eluting with 20% ethyl acetate inhexane. Collection and concentration of appropriate fractions providedthe title compound.

Step C: 2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-bromobenzyl)-imidazole

To a cold (-40° C.) slurry of LiAlH₄ in anhydrous diethyl ether (50 mL),a solution of N-Methoxy-N-methyl2-[(N-tert-butyloxy-carbonyl)-(N-4-bromobenzyl)amino]-2-(biphenyl-4-ylmethyl)acetamide(2.11 g, 3.82 mmol) in THF (10 mL) was added. The resultant mixture wasstirred at -40° C. for 10 min. and allowed to warm up to 0° C. Themixture was then cooled back to -40° C., and quenched with aqueous KHSO₄solution with temperature of the mixture maintained below -30° C. Theresultant mixture was diluted with diethyl ether and stirred at roomtemp for 30 min. The ethereal solution was isolated, washed with brine,dried over anhydrous magnesium sulfate, filtered, and concentrated undervacuum to provide a foamy product.

Without further purification, 0.6 g of the aldehyde obtained from theabove procedure was dissolved in dichloromethane (10 mL) and treatedwith trifluoroacetic acid (2 mL) at room temperature for 15 min. Theresulting mixture was concentrated under vacuum. The residue wasdissolved in a mixture of absolute ethanol and dichloromethane (8 mL,5:1 v/v; pH adjusted to about 4-5 with addition ofdiisopropylethylamine), treated with cyanamide (0.16 g, 3.69 mmol), andheated under reflux for 3 h. The resultant mixture was concentrated, andthe residue subjected to column chromatography on silica gel elutingwith a 1:1 mixture of 5% methanol in chloroform and chloroform saturatedwith ammonia gas. Collection and concentration of appropriate fractionsprovided the title aminoimidazole as white solid.

¹ H NMR (CDCl₃ 300 MHz) δ 7.6-7.1(11H, m), 6.79 (2H, d, J=8.5 Hz), 6.59(1H, s), 4.73 (2H, s), 3.81 (2H, s), and 3.72 (2H, br s) ppm. FAB MS418/420 (MH⁺).

Step D: 2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-cyanobenzyl)imidazole

A mixture of 2-amino-5-(biphenyl-4-ylmethyl)-1-(4-bromo-benzyl)imidazole(114 mg, 0.27 mmol), anhydrous zinc cyanide (19 mg, 0.16 mmol), andanhydrous dimethylfomamide (2 mL) was purged with argon for 20 minutes.Tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.028 mmol) was added,and the resultant solution was stirred under argon at 80° C. for 36hours. The product mixture was concentrated under vacuum, and theresidue subjected to column chromatography on silica gel eluting with a1:1 mixture of 10% methanol in chloroform and chloroform saturated withammonia gas. Collection and concentration of appropriate fractionsprovided the title aminoimidazole as white solid.

Anal. Calcd for C₂₄ H₂₀ N₄ •0.10 CHCl₃ : C, 76.91; H, 5.38; N, 14.89.Found: C, 77.04; H, 5.47; N, 14.78.

Example 72 2-Amino-1-(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)imidazoletrifluoroacetate salt

Step A: N-Methoxy-N-methyl 2-(N-tert-butyloxycarbonylamino)-2-(4-bromobenzyl)acetamide

The title compound was prepared as a white solid using the protocoldescribed in Example 71--Step A, substituting N-Boc 4-biphenyl-alaninewith N-Boc 4-bromophenylalanine.

¹ H NMR (CDCl₃ 300 MHz) δ 7.39 (2H, J 8.5 Hz, d), 7.04 (2H, J 8.5 Hz,d), 5.2 (1H, br s), 4.9 (1H, br s), 3.69 (3H, s), 3.17 (3H, s), 2.9 (2H,m), and 1.39 (9H, s).

Step B: N-Methoxy-N-methyl2-[(N-tert-butyloxycarbonyl)-(N-biphenyl-4-ylmethyl)amino]-2-(4-bromobenzyl)acetamide

The title compound was prepared as a white solid using the protocoldescribed in Example 71--Step B, substituting N-methoxy-N-methyl2-(N-tert-butyloxycarbonylamino)-2-(biphenyl-4-ylmethyl)-acetamide withN-Methoxy-N-methyl2-(N-tert-butyloxycarbonylamino)-2-(4-bromobenzyl)acetamide, and4-bromobenzyl bromide with biphenyl-4-ylmethyl iodide.

Step C: 2-Amino-1-(biphenyl-4-ylmethyl)-5-(4-bromobenzyl)-imidazole

The title compound was prepared as a white solid using the protocoldescribed in Example 71--Step C, substituting N-Methoxy-N-methyl2-[(N-tert-butyloxy-carbonyl)-(N-4-bromobenzyl)amino]-2-(biphenyl-4-ylmethyl)acetamidewith N-Methoxy-N-methyl2-[(N-tert-butyloxycarbonyl)-(N-biphenyl-4-ylmethyl)amino]-2-(4-bromobenzyl)-acetamide.

¹ H NMR (CDCl₃ 300 MHz) δ 7.6-7.3 (8H, m), 7.04-6.97 (4 H, m), 6.53 (1H,s), 4.78 (2H, s), 3.83 (2H, br s), and 3.76 (2H, s) ppm. FAB MS 418/420(MH⁺).

Step D: 2-Amino-1-(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazoletrifluoroacetate salt

The title compound was prepared as a white solid using the protocoldescribed in Example 71--Step D, substituting2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-bromobenzyl)imidazole with2-amino-1-(biphenyl-4-ylmethyl)-5-(4-bromobenzyl)imidazole.

Anal. Calcd for C₂₄ H₂₀ N₄ •1.25 TFA: C, 62.78; H, 4.22; N, 11.05.Found: C, 62.93; H, 4.04; N, 10.68.

Example 73 1-(3-Butylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazolehydrochloride

Step A: (N-tert-butyl)-4-biphenylcarboxamide

To a 1 L round bottomed flask with a stirring bar and a drying tube wasadded 4-biphenylbenzoic acid (35.14 g, 177.26 mmol), CH₂ Cl₂ (500 mL)and oxalyl chloride (17.18 mL, 196.96 mmol). To this well stirredmixture was added 10 drops of DMF. This mixture was stirred at ambienttemperature for 5 h. The solvent and excess oxalyl chloride were removedin vacuo and the solid acid chloride was redissolved in fresh CH₂ Cl₂(500 mL). This solution was cooled to 0° C. and tert-butylamine (23.28mL, 221.58 mmol), Et₃ N (30.88 mL, 221.58 mmol) and 4-DMAP (0.20 g) wereadded sequentially. The cooling bath was allowed to expire and themixture was stirred at ambient temperature for 18 h. The reactionmixture was diluted with an equal volume of CHCl₃ and this solution waswashed successively with 1N HCl, NaHCO₃ solution and brine. Drying(MgSO₄), filtration and removal of the solvent in vacuo gave an offwhite solid. This material was triturated with Et₂ O (100 mL) andcollected on a frit and dried in vacuo to afford the title compound.

¹ H NMR (CDCl₃) δ 1.49 (9H,s), 5.98 (1H, br s), 7.38 (1H, m), 7.45 (2H,t, j=6 Hz), 7.62 (4H, m), 7.80 (2H, d, j=7 Hz).

Step B: (N-tert-butyl)-3-(1-hydroxybutylyl)-4-biphenylcarboxamide

To three necked, 500 mL, oven dried round bottomed flask with a stirringbar, argon inlet, low temperature thermometer and a septum was added(N-tert-butyl)-4-biphenylcarboxamide (5.00 g, 19.66 mmol) and dry THF(200 mL). This solution was cooled to -78° C. and n-butyllithium (16.12mL of a 2.5M solution in hexane, 40.30 mmol) was added with a syringe atdropwise so that the temperature did not exceed -65° C. The cooling bathwas replaced with an ice-H₂ O bath and the reaction was allowed to warmto 0° C. and stir 45 min. The solution was recooled to -78° C. andbutyraldehyde (1.80 mL, 20.00 mmol) was added with a syringe. Thismixture was warmed to 5° C. during which time the mixture becamehomogenous. The mixture was poured into 10% aqueous citric acid andextracted with EtOAc. The organic fraction was washed with aqueousNaHCO₃ solution and brine. Drying (MgSO₄), filtration and removal of thesolvent in vacuo gave a colorless foam. This material waschromatographed on silica gel using 15% EtOAc in hexane as eluant toafford the title compound.

¹ H NMR (CDCl₃) δ 0.95 (3H, t, j=7.5 Hz), 1.36 (1H, m), 1.49 (9H, s),1.50 (1H, m), 1.79 (1H, m), 1.95 (1H, m), 4.58 (1H, m), 4.75 (1H, q, j=7Hz), 6.00 (1H, br s), 7.38 (1H, m), 7.47 (4H, m), 7.59 (3H, m).

Step C: (N-tert-butyl)-3-butyl-4-biphenylcarboxamide

To 500 mL Parr flask was added(N-tert-butyl)-3-(1-hydroxybutyl)-4-biphenylcarboxamide (3.50 g, 10.75mmol), abs EtOH (125 mL) and 10% palladium on carbon (3.50 g). Thismixture was hyrogenolyzed at 60 psig and ambient temperature for 48 h.The catalyst was removed by filtration on a celite pad and the solventwas removed in vacuo. This material was chromatographed on silica gelusing 10% EtOAc in hexane as eluant to afford the title compound as awhite crystalline solid.

¹ H NMR (CDCl₃) δ 0.94 (3H, t, j=7.5 Hz), 1.39 (2H, m), 1.48 (9H, s),1.63 (2H, m), 2.83 (2H, m), 5.60 (1H, br s), 7.38 (1H, m), 7.47 (4H, m),7.59 (3H, m).

Step D: 2-Chloroethyl 3-butyl-4-phenylbenzoate

To a 200 mL round bottomed flask with a stirring bar and a refluxcondenser was added (N-tert-butyl)-3-butyl-4-biphenylcarboxamide (3.17g, 10.24 mmol), ethylene glycol (25 mL) and 12N HCl (25 mL). Thismixture was heated at reflux 72 h. The cooled mixture was extracted withEtOAc and the EtOAc extracts were combined, washed with H₂ O (3×) andbrine. Drying (MgSO₄), filtration and removal of the solvent in vacuogave an oil. This material was chromatographed on silica gel using 30%EtOAc in hexane as eluantto afford the title compound as an oil.

¹ H NMR (CDCl₃) δ 0.95 (3H, T, J=6.4 Hz), 1.41 (2H, m), 1.65 (2H, m),3.04 (2H, dd, j=5.6, 1.0 Hz), 3.82 (2H, t, j=5.6 Hz), 4.58 (2H, t,j=5.6), 7.38 (1H, m), 7.47 (3H, m), 7.62 (2H, m), 8.02 (1H, d, j=8.9Hz).

Step E: 2-Butyl-4-phenylbenzenemethanol

To a 100 mL round bottomed flask with a stirring bar and an argon inletwas added 2-chloroethyl 3-butyl-4-phenylbenzoate (570 mg, 1.80 mmol),THF (9 mL) and LiBH₄ (9 mL of a 2M solution in THF, 18 mmol). Thismixture was heated at reflux for 18 h. The cooled reaction mixture wastreated with 1N HCl and extracted with EtOAc. The combined EtOAcextracts were washed with H₂ O and brine. Drying (MgSO₄), filtration andremoval of the solvent in vacuo gave an oil. This material waschiromatographed on silica gel using 20% EtOAc in hexane as eluant toafford the title compound as a crystalline solid.

¹ H NMR (CDCl₃) δ 0.97 (3H, t, j=7.3), 1.41 (2H, m), 1.59 (2H, m), 2.76(2H, dd, j=5.6, 1.0 Hz), 4.77 (2H, s), 7.35 (1H, m), 7.44 (5H, m), 7.58(2H, m).

Step F: 2-Butyl-4-phenylbenzenemethyl bromide

To a 200 mL round bottomed flask with a stirring bar and an argon inletwas added NBS (675 mg, 3.8 mmol) in 25 ml CH₂ Cl₂. This solution wascooled to 0° C. and was added methylsulfide (0.33 ml, 4.55 mmol). Theresulting suspension was cooled to -20° C. and was added and solution of2-butyl-4-phenylbenzenemethanol (608 mg, 2.53 mmol) in 15 ml CH₂ Cl₂.The reaction mixture was stirred at 0° C. for 3 h. Poured the solutionmixture in 200 ml ice. separated the layers, CH₂ Cl₂ layer was washedwith H2O and brine, dried (MgSO₄), filtration and removed solvent invacuo to afford the title product as an oil.

¹ H NMR (CDCl₃) δ 0.98 (t, 3H), 1.45 (m, 2H), 1.69 (m, 2H), 2.79 (m,2H), 4.6 (s, 2H), 7.36 (m, 1H), 7.43 (m, 4H), 7.58 (d, J=7.32, 2H).

Step G: 1-(3-Butylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazolehydrochloride

To a 50 mL round bottomed flask with a stirring bar and an argon inletwas added 2-Butyl-4-phenylbenzenemethyl bromide (750 mg, 1.70 mmol), and1-trityl-4-(4-cyanobenzyl) imidazole (638 mg, 1.5 mmol) in CH₃ CN (12mL). The mixture was refluxed for 24 hours. The solvent was evaporatedin vacuo. The residue was dissolved in methanol (10 mL), healed atreflux for 4 hour, removal of solvent in vacuo. The residue waspartitioned between EtOAc and sat. aq. NaHCO₃ solution. The organiclayer was dried, (MgSO₄) and the solvent evaporated in vacuo. Theresidue was chromatographed (Silica gel, 3% 2-propanol in CHCl3). Theamine was converted to the HCl salt by treatment with 4.0M HCl in 1,4dioxane. Triturated with EtOAc to afford a white solid.

¹ H NMR (DMSO-d6, 400 MHz) δ 0.90(t, 3H), 1.28(m, 2H), 1.45(m, 2H),2.42(m, 2H), 4.09(s, 2H), 5.14(s, 2H), 6.94(d, J=8.06 Hz, 1H), 7.26(m,1H), 7.40-7.49(m, 7H), 7.56(d, J=6.96 Hz, 2H), 7.68(d, J=7.87 Hz, 2H),8.38(br, s 1H).

Example 74 1-(3-Propylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazolehydrochloride

Title compound was prepared using the procedure described in Example 73substituting propionaldehyde for butyraldehyde in step B.

¹ H NMR (DMSO-d6, 400 MHz) δ 0.91 (t, 3H), 1.46-1.51 (m, 2H), 2.5(m,2H), 4.16(s, 2H), 5.44(s, 3H), 6.69(d, J=7.6 Hz, 1H), 7.31-7.39(m, 4H),7.44-7.48(m, 3H), 7.59-7.63(m, 3H), 7.69(d, J=8.05 Hz, 2H), 9.05(br, s1H).

Example 75 1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazoletrifluoroacetate salt

Step A:1-(4-Cyanobenzyl)-5-[1-chloro-(3-fluoro-4-biphenyl)methyl]imidazole

The alcohol from Example 28 (380 mg. 1 mmol) was dissolved in thionylchloride (500 μl) and the solution was stirred at room temperature for 4hours and then evaporated solution in vacuo to afford title compound.

Step B: 1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazoletrifluoroacetate salt

The chloride from step A was hydrogenolyzed in absolute ethanol (10 mL)over 10% Pd/C (50 mg) in a Parr apparatus at 40 psi (initial) for 6days. The catalyst was filtered off, washed well with EtOH and thesolvent was evaporated. The residue was chromatographed (silica gel,2-5% MeoH--CHCl3) and further purified by preparative HPLC. (gradientelution, 95:5 to 5:95% H₂ O--CH₃ CN containing 0.1% TFA) to afford thetitle compound as a very hygroscopic white solid.

FAB MS 368.13 (MH⁺); H¹ NMR (CD₃ OD, 400 MHz) δ 4.10 (2H,s) 5.54 (2H,s),6.88 (H,dd, J=11.6 and 1.6 Hz), 6.97 (H,dd, J=11.6 and 1.6 Hz), 7.23(2H,d, J=8.8 Hz), 7.30 (H,t, J=8 Hz), 7.30-7.49 (5H,m), 7.52 (H, brs),7.64 (2H,dd, J=6.4 and 1.6 Hz), 9.07 (H, brs)ppm.

Example 76 1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazoletrifluoroacetate salt

Step A: 1-Trityl-4-(4-cyanobenzyl)-2-methylimidazole

The title compound was prepared using the protocol described in Example16, Step C using 1-trityl-4-iodo-2-methylimidazole.

FAB MS 440.27 (MH⁺); H¹ NMR (CDCl₃, 400 MHz) δ 1.61 (3H,s), 3.87 (2H,s),6.45 (H,s), 7.09-7.15 (5H,m), 7.3-7.36 (12H,m), 7.54 (2H,d, J=8 Hz) ppm.

Step B: 1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazoletrifluoroacetate salt

The title compound was prepared using the protocol described in Example2 using the product from Step A above but purified as in Example 3, StepB to give the product as a very hygroscopic white solid.

FAB MS 364.09 (MH⁺); H¹ NMR (CD₃ OD, 500 MHz) δ 2.62 (3H,s), 4.12(2H,s), 5.36 (2H,s), 7.33 (H,s), 7.35-7.55 (13H,m) ppm.

Example 771-(4-Cyanobenzyl)-5-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole

Step A: 1-Trityl-4-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole

A 1.0M solution of EtMgBr in THF (4 mL, 4 mmol) was added to a solutionof 1-trityl-4-iodo-2-metylimidazole (1.8 g, 4 mmol) in dry CH₂ Cl₂ (8mL) at room temperature. After 1 hour a solution of 4-acetylbiphenyl(780 mg, 4 mmol) in dry CH₂ Cl₂ (4 mL) was added and stirring at roomtemperture was continued for 16 hours. The reaction mixture was quenchedwith sat. NH₄ Cl and then the product was extracted into CHCl₃, driedancl the solvent was evaporated. The residue was chromatographed (silicagel 0.5-10% MeOH--CHCl₃) and further purified by crystallization fromCHCl₃ -hexane to afford title compound, mp 231-232° C.

FAB MS 521.25 (MH⁺); H¹ NMR (CDCl₃, 400 MHz) δ 1.60 (3H,s), 1.76 (3H,s),6.65 (H,s), 7.13-7.18 (6H,m), 7.30-7.36 (10H, m), 7.42 (2H, t, J=7.2Hz), 7.51 (4H,s), 7.57 (2H,dd, J=8.4 and 1.2 Hz) ppm.

Step B1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole

The title compound was prepared using the protocol described in Example5, Step C using the product from Step A above and the correspondingamount of 4-cyanobenzyl alcohol. The residue was chromatographed (silicagel, 1.2-5.0% MeOH--CHCl₃) to yield the title compound.

FAB MS 394.16 (MH⁺); H¹ NMR (CDCl₃, 500 MHz) δ 1.95 (3H,s), 2.18 (3H,2),4.98 (H,d, J=17.6 Hz) 5.22 (H,d, J=17.6 Hz), 6.72 (2H, d, J=8.4 Hz),7.16 (H,s), 7.28-7.37 (5H,m), 7.39 (2H,d, J=8.4 Hz), 7.42-7.47 (4H,m)ppm.

Example 78 1-(4-Cyanobenzyl)-5-(4-biphenylmethyl)-2-methylimidazoletrifluoroacetate salt

Step A: 1-Trityl-4-(4-biphenylmethyl)-2-methylimidazole

The title compound was prepared using the protocol described in Example1, Step A except using the corresponding amounts of4-chloromethylbiphenyl and 1-trityl-4-iodo-2-methylimidazole.

FAB MS 491.31 (MH⁺); H¹ NMR (CDCL3, 400 MHz) δ 1.63 (3H,s), 3.88 (2H,s),6.47 (H,s), 7.12-7.16 (6H, m), 7.29-7.34 (12H,m), 7.41 (2H,t, J=7.6 Hz),7.49 (2H,d, J=7.6 Hz) 7.56 (2H, dd, J=8.8 and 0.8 Hz) ppm.

Step B: 1-4-Cyanobenzyl)-5-(4-biphenylmethyl)-2-methylimidazoletrifluoroacetate salt

The title compound was prepared using the protocol described in Example5, Step C using the product from Step A above and the correspondingamount of 4-cyanobenzyl alcohol but purified as in Example 3, Step B.

Anal. Calc'd for C₂₅ H₂₁ N₃ •0.70 H₂ O•0.40 TFA. C, 62.32; H, 4.48; N,7.84. Found: C, 62.36; H, 4.42; N, 7.87; FAB MS 364.09 (MH⁺); H¹ NMR(CD₃ OD, 500 MHz) δ 2.58 (3H,s), 4.05 (2H,s), 5.49 (2H,s), 7.06 (2H, d,J=8.8 Hz), 7.18 (2H, d J=8.8 Hz), 7.33 (H,m), 7.39 (H,s), 7.42 (2H,m),7.43 (2H,m), 7.51 (2H,m), 7.60 (2H,d, J=8.8 Hz) ppm.

Example 79 1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)]ethyl-2-methyl imidazole

The alcohol from Example 77 (181 mg, 460 mmol) dissolved in CH₂ Cl₂ (8mL) and this solution was. added to a mixture of trimethylsilyl chloride(770 mL, 6 mmol) and NaI (900 mg, 6 mmol). The dark mixture was stirredat room temperature for 20 hours. The reaction mixture was distributedbetween H₂ O (100 mL) and CHCl₃ (50 mL). The organic layer was washedwith saturated Na₂ S₂ O₃ and water. The solvent was evaporated and theresidue was chromatographed (silica gel, 2.5-5% CH₃ OH--CHCl₃) to affordthe title compound.

Anal. Calc'd for C₂₆ H₂₃ N₃ •0.15 CHCl₃ ; C, 79.43; H, 5.90; N, 10.63.Found: C, 79.21; H, 5.74; N, 10.06. FAB MS 378.13 (MH⁺); H¹ NMR (CDCl₃,400 MHz) δ 1.59 (3H, d, J=7.2 Hz), 2.27 (3H,s), 3.74 (H,q, J=7.2 Hz).4.76 (H,d, J=18 Hz), 4.93 (H,d, J=18 HZ, 6.83 (2H,d, J=8.4 Hz),7.05-7.09 (3H, m), 7.32-7.36 (H,m) 7.38-7.46 (4H,m) 7.48-7.53 (4H,m)ppm.

Example 801-(4-Cyanobenzyl-5-[1-(4-biphenyl)]vinylidene-2-methylimidazole

The alcohol from Example 77 (59 mg, 150 μmol) was stirred in TFA (1 mL)at 55° C. for 20 hours. The clear solution was then cooled anddistributed between EtOAc and sat. NaHCO₃. The organic layer wasseparated, dried and the solvert was evaporated. The residue waschromatographed (silica gel. 2.5% CH₃ OH--CHCl₃) to afford the titlecompound.

Anal. Calc'd for C₂₆ H₂₁ N₃ •0.05 CHCl₃ •0.25 CH₃ OH; C, 81.10; H, 5.71;N. 10.79; Found: C, 81.43; H, 6.08; N, 10.59. FAB MS 376.43 (MH⁺); H¹NMR (CDCl₃, 400 MHz) δ 2.34 (3H,s), 4.83 (2H,s), 5.32 (H,d, J=1.2 Hz),5.56 (H,d,=1.2 Hz), 6.90 (2H, d, J=8.4 Hz), 7.10 (H,s), 7.26-7.29 (2H,m)7.34-7.39 (H,m), 7.43-7.59 (8H,m) ppm.

Example 811-(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylimidazoletrifluoroacetate salt

Step A: 1-Trityl-4-[(2-(4-biphenyl)]vinylene-2-methyl imidazole

The title compound was prepared using the protocol described in Example30 using 1-trityl-4-iodo-2-methylimidazole. The dark solution was cooledand chromatographed (silica gel, 0.5% MeOH--CHCl₃) and rechromatographed(silica gel, 20% EtOAc-hexane) to give product as a 3:1 mixture of thedesired 1,2 vinylene and 1,1 vinylidene as evidenced by NMR.

FAB MS 503.39 (MH⁺).

Step B: 1-(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylmidazoletrifluoroacetate salt

The title compound was prepared using the protocol described in Example5, Step C using the corresponding amounts of the product from Step Aabove and 4-cyanobenzyl alcohol.

Anal. Calc'd for C₂₆ H₂₁ N₃ •1.25 TFA•0.60 H₂ O: C, 64.73; H, 4.47; N,7.95; Found: C, 64.71; H, 4.47; N. 7.82; FAB MS 376.08 (MH⁺); H¹ NMR(CD₃ OD, 500 Hz) δ 2.67 (3H,s), 5.70 (2H,s), 6.98 (H,d, J=16.7 Hz), 7.29(H,d, J=16.7 Hz), 7.34 (H,m), 7.39-7.46 (4H,m) 7.57 (2H,d, J=7.5 Hz),7.61-7.64 (4H,m) 7.79 (2H, d, J=9 Hz), 7.86 (H,s) ppm.

Example 82

In vitro Inhibition of Ras Farnesyl Transferase

Assays of farnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM [³ H]-farnesyl diphosphate ([³ H]-FPP; 740CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at31° C. for 60 min. Reactions were initiated with FPTase and stopped with1 ml of 1.0 M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach II cell harvester, washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the [³ H]-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention described in the above Example1-31 were tested for inhibitory activity against human FPTase by theassay described above and were found to have IC₅₀ of ≦50 μM.

Example 83

In vivo Ras Farnesylation Assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supplemeted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi[³⁵ S]methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol.43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated Withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfarnesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

Example 84

In vivo Growth Inhibition Assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits farnesyl-proteintransferase of the formula A: ##STR30## wherein: R^(1a) and R^(1b) areindependently selected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, R¹¹ C(O)O--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R²,R³, R⁴ and R⁵ are independently selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) areindependently, selected from:a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹¹ S(O)_(m) NR¹⁰ --,(R¹⁰)₂ NS(O)_(m) --, R¹³ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; anytwo of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --; provided that when R², R³,R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) is unsubstituted orsubstituted heterocycle, attachment of R², R³, R⁴, R⁵, R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to the phenyl ring is through a ring carbon ofthe hererocycle; R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl,heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) aryl orheterocycle, c) halogen, d) HO, ##STR31## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or h)C₁₋₄ perfluoroalkyl; R⁸ is independently selected from:a) hydrogen, b)aryl, substituted aryl, heterocycle, substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a ring carbon of R⁸ ; R⁹ is independently selected from:a)hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,halogen, R¹¹ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; R¹³ is independently selectedfrom hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, --CH₂ N(R¹⁰)₂, benzyland aryl; A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or S(O)_(m) ; V is selected from:a)hydrogen, b) heterocycle, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4carbon atoms are replaced with a a heteroatom selected from O, S, and N,and e) C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ isS(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; provided that when V is heterocycle, attachment of V to R⁸and to A¹ is through a ring carbon of V; W is a heterocycle; X is abond, --CH═CH--, O, --C(═O)--, --C(O)NR⁷ --, --NR⁷ C(O)--, --C(O)O--,--OC(O)--, --C(O)NR⁷ C(O)--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or--S(═O)_(m) --; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p isindependently 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; r is 0 to 5, providedthat r is 0 when V is hydrogen; and t is 0 or 1;or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1 of theformula A: ##STR32## wherein: R^(1a) is independently selected from:hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆alkyl;R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) unsubstituted or substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R², R³, R⁴ and R⁵ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,urisubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl; d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl; d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹¹ S(O)_(m) NR¹⁰ --, (R¹⁰)₂ NS(O)_(m) --, R¹³C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; any two of R^(6a), R^(6b), R^(6c),R^(6d) and R^(6e) on adjacent carbon atoms are combined to form adiradical selected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ --and --(CH₂)₃ --; provided that when R², R³, R⁴, R⁵, R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) is unsubstituted or substituted heterocycle,attachment of R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e)to the phenyl ring is through a ring carbon of the heterocycle; R⁷ isselected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl, aroyl,heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:a) C₁₋₄ alkoxy, b) aryl or heterocycle, c) halogen, d)HO, ##STR33## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or h) C₁₋₄ perfluoroalkyl; R⁸ isindependently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, substituted heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆, alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--,R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a ring carbon of R⁸ ; R⁹ is independently selected from:a)hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F,Cl, R¹¹ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c)C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl, F,Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R^(10C)(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl 2,2,2-trifluoroethyl,benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl a nd2,2,2-trifluoroethyl; R¹³ is independently selected from hydrogen, C₁-C₆ alkyl, 2,2,2-trifluoroethyl, --CH₂ N(R¹⁰)₂, benzyl and aryl; A¹ andA² are independently selected from: a bond, --CH═--CH--, --C.tbd.C--,--C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; V is selectedfrom:a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl,imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl,isoquinolinyl, triazolyl and thienyl, c) aryl, d) C₁ -C₂₀ alkyl whereinfrom 0 to 4 carbon atoms are replaced with a heteroatom selected from O,S, and N, and e) C₂ -C₂₀ alkenyl, and provided that V is not hydrogen ifA¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; provided that when V is heterocycle, attachment of V to R⁸and to A¹ is through a ring carbon of V; W is a heterocycle selectedfrom pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl,oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl; X is a bond,O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷ C(O)--, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --; m is 0, 1 or 2; n is independently0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3;r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;ora pharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 of the formula B: ##STR34## wherein: R^(1a) is independentlyselected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁-C₆ alkyl;R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) unsubstituted or substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R² and R³ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ S(O)_(m) NR¹⁰ --, (R¹⁰)₂ NS(O)_(m) --, R¹³C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; any two of R^(6a), R^(6b), R^(6c),R^(6d) and R^(6e) on adjacent carbon atoms are combined to form adiradical selected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ --and --(CH₂)₃ --; provided that when R², R³, R^(6a), R^(6b), R^(6c),R^(6d) or R^(6e) is unsubstituted or substituted heterocycle, attachmentof R², R³, R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ringis through a ring carbon of the heterocycle; R⁸ is independentlyselected from:a) hydrogen, b) aryl, substituted aryl, heterocycle,substituted heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C((O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;provided that when R⁸ is heterocycle, attachment of R⁸ to V is through aring carbon of R⁸ ; R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆alkyl, trifluoromethyl and halogen; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; R¹² is independentlyselected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substitutedaralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl,substituted aryl, heteroaryl, substituted heteraryl, C₁ -C₆perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; R¹³ isindependently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, --CH₂ N(R¹⁰)₂, benzyl and aryl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ; V is selectedfrom:a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl,imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl,isoquinolinyl, triazolyl and thienyl, c) aryl, d) C₁ -C₂₀ alkyl whereinfrom 0 to 4 carbon atoms are replaced with a heteroatom selected from O,S, and N, and e) C₂ -C₂₀ alkenyl, and provided that V is not hydrogen ifA¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; provided that when V is heterocycle, attachment of V to R⁸and to A¹ is through a ring carbon of V; X is a bond, --CH═CH--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--; m is 0, 1 or 2; n isindependently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and r is 0 to 5,provided that r is 0 when V is hydrogen;or a pharmaceutically acceptablesalt thereof.
 4. The compound according to claim 1 of the formula C:##STR35## wherein: R^(1a) is independently selected from: hydrogen, C₃-C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;R^(1b) isindependently selected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆ alkenyl, c) unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ;R² and R³ are independently selected from:a) hydrogen, b) unsubstitutedor substituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN(R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹O--C(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆alkyl wherein the substituent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, unsubstituted orsubstituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹¹ S(O)_(m) NR¹⁰ --,(R¹⁰)₂ NS(O)_(m) --, R¹³ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; anytwo of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --; provided that when R², R³,R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) is unsubstituted or substitutedheterocycle, attachment of R², R³, R^(6a), R^(6b), R^(6c), R^(6d) orR^(6e) to the phenyl ring is through a ring carbon of the heterecycle;R⁸ is independently selected from:a) hydrogen, b) aryl, substitutedaryl, heterocycle, substituted heterocycle, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl,R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰), R¹⁰ C(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸to V is through a ring carbon of R⁸ ; R^(9a) and R^(9b) areindependently hydrogen, C₁ -C₆ alkyl, trifluoromethyl and halogen; R¹⁰is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; R¹² is independently selected from hydrogen,C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl,heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyland 2,2,2-trifluoroethyl; R¹³ is independently selected from hydrogen,C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, --CH₂ N(R¹⁰)₂, benzyl and aryl; A¹and A² are independently selected from: a bond, --CH═CH--, --C.tbd.C--,--C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; V is selectedfrom:a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl,imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl,isoquinolinyl, triazolyl and thienyl, c) aryl, d) C₁ -C₂₀ alkyl whereinfrom 0 to 4 carbon atoms are replaced with a heteroatom selected from O,S, and N, and e) C₂ -C₂₀ alkenyl, and provided that V is not hydrogen ifA¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; provided that when V is heterocycle, attachment of V to R⁸and to A¹ is through a ring carbon of V; X is a bond, --CH═CH--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--; m is 0, 1 or 2; n isindependently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4, provided that p isnot 0 if X is a bond, --NR¹⁰ C(O)--, --NR¹⁰ -- or O; and r is 0 to 5,provided that r is 0 when V is hydrogen;or a pharmaceutically acceptablesalt thereof.
 5. The compound according to claim 3 of the formula D:##STR36## wherein: R^(1a) is independently selected from: hydrogen, C₃-C₁₀ cycloalkyl or C₁ -C₆ alkyl;R^(1b) is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂,F or C₂ -C₆ alkenyl, c) C₁ -C₆ alkyl unsubstituted or substituted byaryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or--N(R¹⁰)₂ ; R² is selected from:a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R³is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ; R^(6a), R^(6b),R^(6c), R^(6d) and R^(6e) are independently selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e)on adjacent carbon atoms are combined to form a diradical selected from--CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --; providedthat when R², R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) is unsubstitutedor substituted heterocycle, attachment of R², R^(6a), R^(6b), R^(6c),R^(6d) or R^(6e) to the phenyl ring is through a ring carbon of theheterocycle; R⁸ is independently selected from:a) hydrogen, b) aryl,substituted aryl, heterocycle, substituted heterocycle, C₁ -C₆ alkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl,R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; or provided that when R⁸ is heterocycle, attachment ofR⁸ to V is through a ring carbon of R⁸ ; R^(9a) and R^(9b) areindependently hydrogen, halogen, CF₃ or methyl; R¹⁰ is independentlyselected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl andaryl; R¹¹ is independently selected from C₁ -C₆ alkyl and aryl; R¹² isindependently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁-C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substitutedheteroaralkyl, aryl, substituted aryl, heteroaryl, substitutedheteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ; X isa bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--; n is 0or 1; provided that n is not 0 if A¹ is a bond, O, --N(R¹⁰)--, orS(O)_(m) ; m is 0 , 1 or 2; and p is 0, 1, 2, 3 or 4;or thepharmaceutically acceptable salts thereof.
 6. The compound according toclaim 4 of the formula E: ##STR37## wherein: R^(1a) is independentlyselected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl;R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;R² is selected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ aryl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R³ is selected from H, halogen, C₁ -C₆ alky and CF₃; R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R^(6a), R^(6b), R^(6c), R^(6d) andR^(6e) on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --; provided that when R², R^(6a), R^(6b), R^(6c), R^(6d) orR^(6e) is unsubstituted or substituted heterocycle, attachment of R²,R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring is through aring carbon of the heterocycle; R⁸ is independently selected from:a)hydrogen, b) aryl, substituted aryl, heterocycle, substitutedheterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;provided that when R⁸ is heterocycle, attachment of R⁸ to V is through aring carbon of R⁸ ; R^(9a) and R^(9b) are independently hydrogen,halogen, CF₃ or methyl; R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, --CH═CH--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--; n is 0 or 1; m is 0, 1 or2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond orO;or the pharmaceutically acceptable salts thereof.
 7. The compoundaccording to claim 5 of the fonnula F: ##STR38## wherein: R^(1a) isindependently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆alkyl;R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F, c) C₁ -C₆alkyl unsubstituted or substituted by aryl, heterocycle, C₃ -C₁₀cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R² is selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected fiom unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R³ is selected from H, halogen, CH₃ and CF₃ ;R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or provided that when R², R^(6a), R^(6b), R^(6c),R^(6d) or R^(6e) is unsubstituted or substituted heterocycle, attachmentof R², R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring isthrough a ring carbon of the heterocycle; R^(9a) and R^(9b) areindependently hydrogen, halogen, CF₃ or methyl; R¹⁰ is independentlyselected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; R¹² is independentlyselected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substitutedaralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl,substituted aryl, heteroaryl, substituted heteraryl, C₁ -C₆perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond,--CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--; m is 0, 1 or 2;and p is 0, 1, 2, 3 or 4;or the pharmaceutically acceptable saltsthereof.
 8. The compound according to claim 6 of the formula G:##STR39## wherein: R^(1a) is independently selected from: hydrogen, R¹⁰O--, --N(R¹⁰)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;R^(1b) isindependently selected from:a) hydrogen, b) aryl, heterocycle or C₃ -C₁₀cycloalkyl, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;R² is selected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R³ is selected from H, halogen, CH₃ and CF₃ ;R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R^(6a), R^(6b), R^(6c), R^(6d) andR^(6e) on adjacent carbon atoms are combined to from a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --; provided that when R², R^(6a), R^(6b) R^(6c), R^(6d) orR^(6e) is unsubstituted or substituted heterocycle, attachment of R²,R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to the phenyl ring is through aring carbon of the heterocycle; R^(9a) and R^(9b) are independentlyhydrogen, halogen, CF₃ or methyl; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; R¹² is independentlyselected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substitutedaralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl,substituted aryl, heteroaryl, substituted heteraryl, C₁ -C₆perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A¹ is selectedfrom: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ; m is 0, 1 or 2; andn is 0 or 1;or the pharmaceutically acceptable salts thereof.
 9. Acompound which inhibits farnesyl-protein transferase whichis:1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Trifluoromethoxy-4-biphenylmethyl)-5-(1-cyanobenzyl) imidazole1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanolbenzyl)imidazole1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazole1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole5-(4-Cyanophenyloxy)-1-(2'-methyl-4-biphenylmethyl)-imidazole5-(4-Biphenyloxy)-1-(4-cyanobenzyl)-imidazole5-(2'-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazole5-(4-(3',5'-dichloro)biphenylmethyl)-1-(4-cyanobenzyl)imidazole1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole1-(4-Biphenylmethyl)-5-(1-(R,S)-hydroxy-1-(4-cyanophenyl)methylimidazole 1-(4-Biphenylmethyl)-5-(1-(R,S)-amino-1-(4-cyanophenyl)methylimidazole1-(4-biphenylmethyl)-5-(1-(R,S)-methoxy-1-(4-cyanophenyl)-methylimidazole1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl)-imidazole1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-biphenyl)methyl-imidazole5-(2-[1,1'-Biphenyl]vinylene)-1-(4-cyanobenzyl)imidazole1-(4-Biphenylmethyl)-5-(4-bromophenyloxy)-inidazole1-(3'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(4'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(3'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'3'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'4'-Dichloro-4-biphenylmethyl)-5-(4-cyanolenzyl)imidazole1-(2'5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2'-Fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-(2'-Trifluoromethylphenyl)-2-Chlorophenylmethyl)-5-(4-cyanobenzyl)imidazole1-{1-(4-(2'-trifluoromethylphenyl)phenyl)ethyl}-5-(4-cyanobenzyl)imidazole 1-(2'-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl)imidazole1-(2'-N-t-Butoxycarbonylamino-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Acetylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2'-Methylsulfonylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Ethylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2'-Phenylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2'-Glycinylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2'-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl) imidazole1-(2'-Methyl-4-biphenylmethyl)-4-chloro 5-(4-cyanobenzyl) imidazole1-(3'-Chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole1-(3'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3'-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Chloro-4'-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Ethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-(2-Propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-(2-Methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2'-Ethyl-4-biphenylmethyl)-5-(4-(1H-tetrazol-5-yl))benzyl)imidazole1-[1-(4-Cyanobenzyl)imidazol-5-ylmethoxy]-4-(2'-methylphenyl)-2-(3-N-phthalimido-1-propyl)benzene1-(3',5'-Ditrifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3',5'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3',5'-Dimethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole1-(3-Aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-Cyanobenzyl)-2-methyl-5-(2'-methylbiphenyl-4-yloxy)imidazole5-(4-Cyanobenzyl)-1-(3-cyano-2'-trifluoromethylbiphenyl-4-ylmethyl)-imidazole2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-cyanobenzyl)imidazole2-Amino-1-(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-Butylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole1-(3-Propylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazole1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazole1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole1-(4-Cyanobenzyl)-5-(4-biphenylmethyl)-2-methylimidazole1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)]ethyl-2-methyl imidazole1-(4-Cyanobenzyl-5-[1-(4-biphenyl)]vinylidene-2-methylimidazoleor1-(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylimidazoleor apharmaceutically acceptable salt or optical isomer thereof.
 10. Thecompound according to claim 9 whichis:1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole ##STR40##or a pharmaceutically acceptable salt or optical isomer thereof.
 11. Thecompound according to (claim 9 whichis:1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole ##STR41##or a pharmaceutically acceptable salt or optical isomer thereof.
 12. Thecompound according to claim 9 whichis:1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl)imidazole##STR42## or a pharmaceutically acceptable salt or optical isomerthereof.
 13. The compound according to claim 9 whichis:1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole ##STR43##or a pharmaceutically acceptable salt or optical isomer thereof.
 14. Thecompound according to claim 9 whichis:5-(2'-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazole ##STR44## or apharmaceutically acceptable salt or optical isomer thereof.
 15. Thecompound according to claim 9 whichis:1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl)-imidazole##STR45## or a pharmaceutically acceptable salt or optical isomerthereof.
 16. The compound according to claim 9 whichis:1-(2',5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole##STR46## or a pharmaceutically acceptable salt or optical isomerthereof.
 17. The compound according to claim 9 which is:1-(3'-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole##STR47## or a pharmaceutically acceptable salt or optical isomerthereof.
 18. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 1. 19. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 3. 20. A pharmaceuticalcomposition comprising a pharmaceutical carrier, and dispersed therein,a therapeutically effective amount of a compound of claim
 4. 21. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 9. 22. A method for inhibiting farnesyl-protein transferase whichcomprises administering to a mammal in reed thereof a therapeuticallyeffective amount of a composition of claim
 18. 23. A method forinhibiting farnesyl-protein transferase which comprises administering toa mammal in need thereof a therapeutically effective amount of acomposition of claim
 19. 24. A method for inhibiting farnesyl-proteintransferase which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 20. 25. Amethod for inhibiting farnesyl-protein transferase which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 21. 26. A method for treating cancerwhich comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 18. 27. Amethod for treating cancer which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 19. 28. A method for treating cancer which comprises administeringto a mammal in need thereof a therapeutically effective amount of acomposition of claim
 20. 29. A method for treating cancer whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 21. 30. A method for treatingneurofibromin benign proliferative disorder which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 18. 31. A method for treating blindnessrelated to retinal vascularization which comprises administering to amammal in need thereof a therapeutically effective amount of acomposition of claim
 18. 32. A method for treating infections fromhepatitis delta and related viruses which comprises administering to amammal in need thereof a therapeutically effective amount of acomposition of claim
 18. 33. A method for preventing restenosis whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 18. 34. A method for treatingpolycystic kidney disease which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 18. 35. A pharmaceutical composition made by combining thecompound of claim 1 and a pharmaceutically acceptable carrier.
 36. Aprocess for making a pharmaceutical composition comprising combining acompound of claim 1 and a pharmaceutically acceptable carrier.